Imidazo-pyrazinyl derivatives useful as soluble guanylate cyclase activators

ABSTRACT

A compound of Formula I or a pharmaceutically acceptable salt thereof, are capable of modulating the body&#39;s production of cyclic guanosine monophosphate (“cGMP”) and are generally suitable for the therapy and prophylaxis of diseases which are associated with a disturbed cGMP balance. The invention furthermore relates to processes for preparing compounds of Formula I, or pharmaceutically acceptable salt thereofs, for their use in the therapy and prophylaxis of the abovementioned diseases and for preparing pharmaceuticals for this purpose, and to pharmaceutical compositions which comprise compounds of Formula I or pharmaceutically acceptable salts thereof.

BACKGROUND OF THE INVENTION

Cyclic GMP (cGMP) is an important intracellular messenger which triggersa multitude of different effects via the modulation of cGMP-dependentprotein kinases, phosphodiesterases and ion channels. Examples are therelaxation of smooth muscles, the inhibition of thrombocyte activationand the inhibition of the proliferation of smooth-muscle cells and ofleukocyte adhesion. cGMP is produced by particulate and solubleguanylate cyclases as a response to a number of extracellular andintracellular stimuli. In the case of the particulate guanylatecyclases, stimulation is essentially effected by peptidic messengers,such as the atrial natriuretic peptide or the cerebral natriureticpeptide. The soluble guanylate cyclases (“sGC”), which are cytosolicheterodimeric heme proteins, in contrast, are essentially regulated by afamily of low-molecular-weight factors which are formed enzymatically.The most important stimulant is nitrogen monoxide (“NO”) or a closelyrelated species. The function of other factors such as carbon monoxideor the hydroxyl radical is still largely unclear. The binding of NO tothe heme with formation of a penta-coordinate heme-nitrosyl complex isproposed as the mechanism of the activation by NO. The associatedrelease of the histidine which is bound in the basal state to the ironconverts the enzyme into the active confirmation.

Active soluble guanylate cyclases are each composed of an α and a βsubunit. Several subunit subtypes have been described which differ fromone another with respect to sequence, tissue-specific distribution andexpression in different development stages. The subtypes α₁ and β₁ aremainly expressed in brain and lung, while β₂ is found in particular inliver and kidney. The subtype α₂ was shown to be present in human fetalbrain. The subunits referred to as α₃ and β₃ were isolated from humanbrain and are homologous to α₁ and β₁. More recent works indicate anα_(2i) subunit which contains an insert in the catalytic domain. Allsubunits show great homologies in the region of the catalytic domain.The enzymes presumably contain one heme per heterodimer, which is boundvia β₁-Cys-78 and/or β₁-His-105 and is part of the regulatory center.

Under pathologic conditions, the formation ofguanylate-cyclase-activating factors can be reduced, or theirdegradation may be promoted owing to the increased occurrence of freeradicals. The resulting reduced activation of the sGC leads, via aweakening of the respective cGMP-mediated cellular response, for exampleto an increase of the blood pressure, to platelet activation or toincreased cell proliferation and cell adhesion. As a consequence,formation of endothelial dysfunction, atherosclerosis, hypertension,stable or unstable angina pectoris, thrombosis, myocardial infarction,strokes or erectile dysfunction results. Pharmacological stimulation ofsGC offers a possibility to normalize cGMP production and thereforemakes possible the treatment and/or prevention of such disorders.

For the pharmacological stimulation of the sGC, use has been made ofcompounds whose activity is based on an intermediate NO release, forexample organic nitrates. The drawback of this treatment is thedevelopment of tolerance and a reduction of activity, and the higherdosage which is required because of this.

Various sGC stimulators which do not act via NO release were describedby Vesely in a series of publications. However, the compounds, most ofwhich are hormones, plant hormones, vitamins or natural compounds suchas, for example, lizard poisons, predominantly only have weak effects onthe cGMP formation in cell lysates. D. L. Vesely, Eur. J. Clin. Invest.,vol. 15, 1985, p. 258; D. L. Vesely, Biochem. Biophys. Res. Comm., vol.88, 1979, p. 1244. A stimulation of heme-free guanylate cyclase byprotoporphyrin IX was demonstrated by Ignarro et al., Adv. Pharmacol.,vol. 26, 1994, p. 35. Pettibone et al., Eur. J. Pharmacol., vol. 116,1985 p. 307, described an antihypertensive action of diphenyliodoniumhexafluorophosphate and attributed this to a stimulation of sGC.According to Yu et al., Brit. J. Pharmacol, vol. 114, 1995, p. 1587,isoliquiritigenin, which has a relaxing action on isolated rat aortas,also activates sGC. Ko et al., Blood vol. 84, 1994, p. 4226, Yu et al.,Biochem. J. vol. 306, 1995, p. 787, and Wu et al., Brit. J. Pharmacol.vol. 116, 1995, p. 1973, demonstrated a sGC-stimulating activity of1-benzyl-3-(5-hydroxymethyl-2-furyl)indazole and demonstrated anantiproliferative and thrombocyte-inhibiting action. Pyrazoles and fusedpyrazoles which exhibit a sGC-stimulating activity are described inEuropean Patent Application No. 908,456 and German Patent ApplicationNo. 19,744,027.

It has now been found that the compounds of the present invention effecta strong activation of soluble guanylate cyclase and are thereforesuitable for the therapy and prophylaxis of disorders which areassociated with a low cGMP level.

SUMMARY OF THE INVENTION

The present invention relates to compounds which activate solubleguanylate cyclase and are valuable pharmaceutically active compounds forthe therapy and prophylaxis of diseases, for example for cardiovasculardiseases such as hypertension, heart failure, pulmonary hypertension,angina pectoris, diabetes, cardiac insufficiency, thrombosis, chronickidney disease, fibrosis or atherosclerosis. The compounds of Formula I

are capable of modulating the body's production of cyclic guanosinemonophosphate (“cGMP”) and may be suitable for the therapy andprophylaxis of diseases which are associated with a disturbed cGMPbalance. The invention furthermore relates to processes for preparingcompounds of Formula I, to the use of such compounds for the therapy andprophylaxis of the abovementioned diseases and for preparingpharmaceuticals for this purpose, and to pharmaceutical compositionswhich comprise compounds of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compounds having structural FormulaI:

or a pharmaceutically acceptable salt thereof wherein:

-   C* indicates a potential chiral carbon atom;-   X is    -   (1) O,    -   (2) NH, or    -   (3) S;-   R¹ is    -   (1) phenyl unsubstituted or substituted by 1 to 3 halo,    -   (2) (C₁₋₆)alkyl unsubstituted or substituted by (C₁₋₃)alkyl,    -   (3) halo(C₁₋₆)alkyl,    -   (4) (C₃₋₇)cycloalkyl unsubstituted or substituted by 1 to 2        halo,    -   (5) 5- or 6-membered heteroaryl containing 1, 2, or 3        heteroatoms independently selected from N, O and S, wherein the        heteroaryl is unsubstituted or substituted by 1 to 2 halo,        (C₁₋₃)alkyl, or halo(C₁₋₃)alkyl,    -   (6) —(C₁₋₃)alkyl-(C₃₋₇)cycloalkyl is unsubstituted or        substituted by 1 to 2 (C₁₋₃)alkyl, or halo groups,    -   (7) —(C₁₋₃)alkyl-phenyl, wherein phenyl is unsubstituted or        substituted by one to three halo, or    -   (8) —(C₁₋₃)alkyl-heterocyclyl containing 1 or 2 heteroatoms        independently selected from N and O, wherein the heterocyclyl is        a 4-7 membered ring;-   R² is    -   (1) (C₁₋₃)alkyl, or    -   (2) (C₃₋₇)cycloalkyl;-   R³ is    -   (1) phenyl unsubstituted or substituted by 1 to 2 halo,    -   (2) five- or six-membered heteroaryl containing 1, 2, or 3        heteroatoms independently selected from N, O and S heteroatoms,        wherein heteroaryl is unsubstituted or substituted by 1 to 2        halo, or    -   (3) (C₁₋₆)alkyl; and-   R⁴ is    -   (1) hydrogen,    -   (2) (C₁₋₃)alkyl,    -   (3) halo(C₁₋₃)alkyl, or    -   (4) (C₃₋₆)cycloalkyl.

In one embodiment, R¹ is (C₁₋₆)alkyl; halo(C₁₋₆)alkyl; (C₃₋₇)cycloalkylunsubstituted or substituted by 1 to 2 halo;—(C₁₋₃)alkyl-(C₃₋₇)cycloalkyl, wherein the cycloalkyl is unsubstitutedor substituted by 1 to 2 (C₁₋₃)alkyl, or halo; or—(C₁₋₃)alkyl-heterocyclyl containing 1 to 2 heteroatoms independentlyselected from N and O, wherein the heterocyclyl is a 4-7 membered ring.

In one class of this embodiment, R³ is phenyl unsubstituted orsubstituted by one to two halo.

In one subclass of this class, X is O. In a sub-subclass of this class,R⁴ is hydrogen.

In one subclass of this class, X is S. In a sub-subclass of this class,R⁴ is hydrogen.

In one subclass of this class, X is NH. In a sub-subclass of this class,R⁴ is hydrogen.

In one class of this embodiment, R³ is six-membered heteroarylcontaining 1 or 2 N heteroatoms, wherein heteroaryl is unsubstituted orsubstituted by 1 to 2 halo.

In one subclass of this class, X is O. In a sub-subclass of this class,R⁴ is hydrogen.

In one subclass of this class, X is S. In a sub-subclass of this class,R⁴ is hydrogen.

In one subclass of this class, X is NH. In a sub-subclass of this class,R⁴ is hydrogen.

In one class of this embodiment, R³ is (C₁₋₆)alkyl.

In one subclass of this class, X is O. In a sub-subclass of this class,R⁴ is hydrogen.

In one subclass of this class, X is S. In a sub-subclass of this class,R⁴ is hydrogen.

In one subclass of this class, X is NH. In a sub-subclass of this class,R⁴ is hydrogen.

In one embodiment, R¹ is phenyl unsubstituted or substituted by 1 to 3halo; 6-membered heteroaryl containing 1 or 2 N heteroatoms, wherein theheteroaryl is unsubstituted or substituted by 1 to 2 halo, (C₁₋₃)alkyl,or halo(C₁₋₃)alkyl; or —(C₁₋₃)alkyl-phenyl, wherein phenyl isunsubstituted or substituted by one to three halo.

In one class of this embodiment, R³ is phenyl unsubstituted orsubstituted by 1 to 2 halo.

In one subclass of this class, X is O. In a sub-subclass of this class,R⁴ is hydrogen.

In one subclass of this class, X is S. In a sub-subclass of this class,R⁴ is hydrogen.

In one subclass of this class, X is NH. In a sub-subclass of this class,R⁴ is hydrogen.

In one class of this embodiment, R³ is six-membered heteroarylcontaining 1 or 2 N heteroatoms, wherein heteroaryl is unsubstituted orsubstituted by one to two halo.

In one subclass of this class, X is O. In a sub-subclass of this class,R⁴ is hydrogen.

In one subclass of this class, X is S. In a sub-subclass of this class,R⁴ is hydrogen.

In one subclass of this class, X is NH. In a sub-subclass of this class,R⁴ is hydrogen.

In one class of this embodiment, R³ is (C₁₋₆)alkyl.

In one subclass of this class, X is O. In a sub-subclass of this class,R⁴ is hydrogen.

In one subclass of this class, X is S. In a sub-subclass of this class,R⁴ is hydrogen.

In one subclass of this class, X is NH. In a sub-subclass of this class,R⁴ is hydrogen.

In one embodiment, R¹ is phenyl unsubstituted or substituted by 1 to 3halo.

In one class of this embodiment, R³ is phenyl unsubstituted orsubstituted by one to two halo.

In one subclass of this class, X is O. In a sub-subclass of this class,R⁴ is hydrogen.

In one subclass of this class, X is S. In a sub-subclass of this class,R⁴ is hydrogen.

In one subclass of this class, X is NH. In a sub-subclass of this class,R⁴ is hydrogen.

In one class of this embodiment, R³ is six-membered heteroarylcontaining 1 or 2 N heteroatoms, wherein heteroaryl is unsubstituted orsubstituted by 1 to 2 halo.

In one subclass of this class, X is O. In a sub-subclass of this class,R⁴ is hydrogen.

In one subclass of this class, X is S. In a sub-subclass of this class,R⁴ is hydrogen.

In one subclass of this class, X is NH. In a sub-subclass of this class,R⁴ is hydrogen.

In one class of this embodiment, R³ is (C₁₋₆)alkyl.

In one subclass of this class, X is O. In a sub-subclass of this class,R⁴ is hydrogen.

In one subclass of this class, X is S. In a sub-subclass of this class,R⁴ is hydrogen.

In one subclass of this class, X is NH. In a sub-subclass of this class,R⁴ is hydrogen.

In one embodiment, R¹ is (C₁₋₆)alkyl.

In one class of this embodiment, R³ is phenyl unsubstituted orsubstituted by 1 to 2 halo.

In one subclass of this class, X is O. In a sub-subclass of this class,R⁴ is hydrogen.

In one subclass of this class, X is S. In a sub-subclass of this class,R⁴ is hydrogen.

In one subclass of this class, X is NH. In a sub-subclass of this class,R⁴ is hydrogen.

In one class of this embodiment, R³ is six-membered heteroarylcontaining 1 or 2 N heteroatoms, wherein heteroaryl is unsubstituted orsubstituted by 1 to 2 halo.

In one subclass of this class, X is O. In a sub-subclass of this class,R⁴ is hydrogen.

In one subclass of this class, X is S. In a sub-subclass of this class,R⁴ is hydrogen.

In one subclass of this class, X is NH. In a sub-subclass of this class,R⁴ is hydrogen.

In one class of this embodiment, R³ is (C₁₋₆)alkyl.

In one subclass of this class, X is O. In a sub-subclass of this class,R⁴ is hydrogen.

In one subclass of this class, X is S. In a sub-subclass of this class,R⁴ is hydrogen.

In one subclass of this class, X is NH. In a sub-subclass of this class,R⁴ is hydrogen.

In one embodiment, R¹ is halo(C₁₋₆)alkyl.

In one class of this embodiment, R³ is phenyl unsubstituted orsubstituted by 1 to 2 halo.

In one subclass of this class, X is O. In a sub-subclass of this class,R⁴ is hydrogen.

In one subclass of this class, X is S. In a sub-subclass of this class,R⁴ is hydrogen.

In one subclass of this class, X is NH. In a sub-subclass of this class,R⁴ is hydrogen.

In one class of this embodiment, R³ is six-membered heteroarylcontaining 1 or 2 N heteroatoms, wherein heteroaryl is unsubstituted orsubstituted by 1 to 2 halo.

In one subclass of this class, X is O. In a sub-subclass of this class,R⁴ is hydrogen.

In one subclass of this class, X is S. In a sub-subclass of this class,R⁴ is hydrogen.

In one subclass of this class, X is NH. In a sub-subclass of this class,R⁴ is hydrogen.

In one class of this embodiment, R³ is (C₁₋₆)alkyl.

In one subclass of this class, X is O. In a sub-subclass of this class,R⁴ is hydrogen.

In one subclass of this class, X is S. In a sub-subclass of this class,R⁴ is hydrogen.

In one subclass of this class, X is NH. In a sub-subclass of this class,R⁴ is hydrogen.

In one embodiment, R¹ is (C₃₋₇)cycloalkyl unsubstituted or substitutedby 1 to 2 halo.

In one class of this embodiment, R³ is phenyl unsubstituted orsubstituted by 1 to 2 halo.

In one subclass of this class, X is O. In a sub-subclass of this class,R⁴ is hydrogen.

In one subclass of this class, X is S. In a sub-subclass of this class,R⁴ is hydrogen.

In one subclass of this class, X is NH. In a sub-subclass of this class,R⁴ is hydrogen.

In one class of this embodiment, R³ is six-membered heteroarylcontaining 1 or 2 N heteroatoms, wherein heteroaryl is unsubstituted orsubstituted by 1 to 2 halo.

In one subclass of this class, X is O. In a sub-subclass of this class,R⁴ is hydrogen.

In one subclass of this class, X is S. In a sub-subclass of this class,R⁴ is hydrogen.

In one subclass of this class, X is NH. In a sub-subclass of this class,R⁴ is hydrogen.

In one class of this embodiment, R³ is (C₁₋₆)alkyl.

In one subclass of this class, X is O. In a sub-subclass of this class,R⁴ is hydrogen.

In one subclass of this class, X is S. In a sub-subclass of this class,R⁴ is hydrogen.

In one subclass of this class, X is NH. In a sub-subclass of this class,R⁴ is hydrogen.

In one embodiment, R¹ is 5- or 6-membered heteroaryl containing 1, 2, or3 heteroatoms independently selected from N, O and S, wherein theheteroaryl is unsubstituted or substituted by 1 to 2 halo, (C₁₋₃)alkyl,or halo(C₁₋₃)alkyl.

In one class of this embodiment, R³ is phenyl unsubstituted orsubstituted by 1 to 2 halo.

In one subclass of this class, X is O. In a sub-subclass of this class,R⁴ is hydrogen.

In one subclass of this class, X is S. In a sub-subclass of this class,R⁴ is hydrogen.

In one subclass of this class, X is NH. In a sub-subclass of this class,R⁴ is hydrogen.

In one class of this embodiment, R³ is six-membered heteroarylcontaining 1 or 2 N heteroatoms, wherein heteroaryl is unsubstituted orsubstituted by 1 to 2 halo.

In one subclass of this class, X is O. In a sub-subclass of this class,R⁴ is hydrogen.

In one subclass of this class, X is S. In a sub-subclass of this class,R⁴ is hydrogen.

In one subclass of this class, X is NH. In a sub-subclass of this class,R⁴ is hydrogen.

In one class of this embodiment, R³ is (C₁₋₆)alkyl.

In one subclass of this class, X is O. In a sub-subclass of this class,R⁴ is hydrogen.

In one subclass of this class, X is S. In a sub-subclass of this class,R⁴ is hydrogen.

In one subclass of this class, X is NH. In a sub-subclass of this class,R⁴ is hydrogen.

In one embodiment, R¹ is —(C₁₋₃)alkyl-(C₃₋₇)cycloalkyl, wherein thecycloalkyl is unsubstituted or substituted by 1 to 2 (C₁₋₃)alkyl, orhalo.

In one class of this embodiment, R³ is phenyl unsubstituted orsubstituted by 1 to 2 halo.

In one subclass of this class, X is O. In a sub-subclass of this class,R⁴ is hydrogen.

In one subclass of this class, X is S. In a sub-subclass of this class,R⁴ is hydrogen.

In one subclass of this class, X is NH. In a sub-subclass of this class,R⁴ is hydrogen.

In one class of this embodiment, R³ is six-membered heteroarylcontaining 1 or 2 N heteroatoms, wherein heteroaryl is unsubstituted orsubstituted by 1 to 2 halo.

In one subclass of this class, X is O. In a sub-subclass of this class,R⁴ is hydrogen.

In one subclass of this class, X is S. In a sub-subclass of this class,R⁴ is hydrogen.

In one subclass of this class, X is NH. In a sub-subclass of this class,R⁴ is hydrogen.

In one class of this embodiment, R³ is (C₁₋₆)alkyl.

In one subclass of this class, X is O. In a sub-subclass of this class,R⁴ is hydrogen.

In one subclass of this class, X is S. In a sub-subclass of this class,R⁴ is hydrogen.

In one subclass of this class, X is NH. In a sub-subclass of this class,R⁴ is hydrogen.

In one embodiment, R¹ is —(C₁₋₃)alkyl-phenyl, wherein phenyl isunsubstituted or substituted by 1 to 3 halo.

In one class of this embodiment, R³ is phenyl unsubstituted orsubstituted by 1 to 2 halo.

In one subclass of this class, X is O. In a sub-subclass of this class,R⁴ is hydrogen.

In one subclass of this class, X is S. In a sub-subclass of this class,R⁴ is hydrogen.

In one subclass of this class, X is NH. In a sub-subclass of this class,R⁴ is hydrogen.

In one class of this embodiment, R³ is six-membered heteroarylcontaining 1 or 2 N heteroatoms, wherein heteroaryl is unsubstituted orsubstituted by 1 to 2 halo.

In one subclass of this class, X is O. In a sub-subclass of this class,R⁴ is hydrogen.

In one subclass of this class, X is S. In a sub-subclass of this class,R⁴ is hydrogen.

In one subclass of this class, X is NH. In a sub-subclass of this class,R⁴ is hydrogen.

In one class of this embodiment, R³ is (C₁₋₆)alkyl.

In one subclass of this class, X is O. In a sub-subclass of this class,R⁴ is hydrogen.

In one subclass of this class, X is S. In a sub-subclass of this class,R⁴ is hydrogen.

In one subclass of this class, X is NH. In a sub-subclass of this class,R⁴ is hydrogen.

In one embodiment, R¹ is —(C₁₋₃)alkyl-heterocyclyl containing 1 or 2heteroatoms independently selected from the group consisting of N and O,wherein the heterocyclyl is a 4-7 membered ring.

In one class of this embodiment, R³ is phenyl unsubstituted orsubstituted by 1 to 2 halo.

In one subclass of this class, X is O. In a sub-subclass of this class,R⁴ is hydrogen.

In one subclass of this class, X is S. In a sub-subclass of this class,R⁴ is hydrogen.

In one subclass of this class, X is NH. In a sub-subclass of this class,R⁴ is hydrogen.

In one class of this embodiment, R³ is six-membered heteroarylcontaining 1 or 2 N heteroatoms, wherein heteroaryl is unsubstituted orsubstituted by 1 to 2 halo.

In one subclass of this class, X is O. In a sub-subclass of this class,R⁴ is hydrogen.

In one subclass of this class, X is S. In a sub-subclass of this class,R⁴ is hydrogen.

In one subclass of this class, X is NH. In a sub-subclass of this class,R⁴ is hydrogen.

In one class of this embodiment, R³ is (C₁₋₆)alkyl.

In one subclass of this class, X is O. In a sub-subclass of this class,R⁴ is hydrogen.

In one subclass of this class, X is S. In a sub-subclass of this class,R⁴ is hydrogen.

In one subclass of this class, X is NH. In a sub-subclass of this class,R⁴ is hydrogen.

In one embodiment, R³ is phenyl unsubstituted or substituted by 1 to 2halo.

In one class of this embodiment, R² is a (C₁₋₃)alkyl.

In one subclass of this class, X is O. In one sub-subclass of thissubclass, R⁴ is hydrogen.

In one subclass of this class, X is S. In one sub-subclass of thissubclass, R⁴ is hydrogen.

In one subclass of this class, X is NH. In one sub-subclass of thissubclass, R⁴ is hydrogen.

In one class of this embodiment, R² is a (C₃₋₇)cycloalkyl.

In one subclass of this class, X is O. In one sub-subclass of thissubclass, R⁴ is hydrogen.

In one subclass of this class, X is S. In one sub-subclass of thissubclass, R⁴ is hydrogen.

In one subclass of this class, X is NH. In one sub-subclass of thissubclass, R⁴ is hydrogen.

In one embodiment, R³ is a five- or six-membered heteroaryl containing1, 2, or 3 heteroatoms independently selected from N, O and Sheteroatoms, wherein heteroaryl is unsubstituted or substituted by 1 to2 halo.

In one class of this embodiment, R² is a (C₁₋₃)alkyl.

In one subclass of this class, X is O. In one sub-subclass of thissubclass, R⁴ is hydrogen.

In one subclass of this class, X is S. In one sub-subclass of thissubclass, R⁴ is hydrogen.

In one subclass of this class, X is NH. In one sub-subclass of thissubclass, R⁴ is hydrogen.

In one class of this embodiment, R² is a (C₃₋₇)cycloalkyl.

In one subclass of this class, X is O. In one sub-subclass of thissubclass, R⁴ is hydrogen.

In one subclass of this class, X is S. In one sub-subclass of thissubclass, R⁴ is hydrogen.

In one subclass of this class, X is NH. In one sub-subclass of thissubclass, R⁴ is hydrogen.

In one embodiment, R³ is a six-membered heteroaryl containing 1 or 2 Nheteroatoms, wherein the heteroaryl is unsubstituted or substituted by 1to 2 halo.

In one class of this embodiment, R² is a (C₁₋₃)alkyl.

In one subclass of this class, X is O. In one sub-subclass of thissubclass, R⁴ is hydrogen.

In one subclass of this class, X is S. In one sub-subclass of thissubclass, R⁴ is hydrogen.

In one subclass of this class, X is NH. In one sub-subclass of thissubclass, R⁴ is hydrogen.

In one class of this embodiment, R² is a (C₃₋₇)cycloalkyl.

In one subclass of this class, X is O. In one sub-subclass of thissubclass, R⁴ is hydrogen.

In one subclass of this class, X is S. In one sub-subclass of thissubclass, R⁴ is hydrogen.

In one subclass of this class, X is NH. In one sub-subclass of thissubclass, R⁴ is hydrogen.

In one embodiment, R³ is (C₁₋₆)alkyl.

In one class of this embodiment, R² is a (C₁₋₃)alkyl.

In one subclass of this class, X is O. In one sub-subclass of thissubclass, R⁴ is hydrogen.

In one subclass of this class, X is S. In one sub-subclass of thissubclass, R⁴ is hydrogen.

In one subclass of this class, X is NH. In one sub-subclass of thissubclass, R⁴ is hydrogen.

In one class of this embodiment, R² is a (C₃₋₇)cycloalkyl.

In one subclass of this class, X is O. In one sub-subclass of thissubclass, R⁴ is hydrogen.

In one subclass of this class, X is S. In one sub-subclass of thissubclass, R⁴ is hydrogen.

In one subclass of this class, X is NH. In one sub-subclass of thissubclass, R⁴ is hydrogen.

In one embodiment, R¹ is

In one class of this embodiment, R³ is methyl,

In one subclass of this class, R² is methyl or cyclopropyl.

In one sub-subclass of this subclass, X is O, NH, or S.

In one sub-sub-subclass of this sub-subclass, R⁴ is hydrogen,trifluoromethyl, or cyclopropyl.

In one embodiment, R³ is methyl,

In one class of this embodiment, R² is methyl.

In one subclass of this class, X is O. In one sub-subclass of thissubclass, R⁴ is hydrogen. In one sub-subclass of this subclass, R⁴ istrifluoromethyl. In one sub-subclass of this subclass, R⁴ iscyclopropyl.

In one subclass of this class, X is NH. In one sub-subclass of thissubclass, R⁴ is hydrogen. In one sub-subclass of this subclass, R⁴ istrifluoromethyl. In one sub-subclass of this subclass, R⁴ iscyclopropyl.

In one subclass of this class, X is S. In one sub-subclass of thissubclass, R⁴ is hydrogen. In one sub-subclass of this subclass, R⁴ istrifluoromethyl. In one sub-subclass of this subclass, R⁴ iscyclopropyl.

In one class of this embodiment, R² is cyclopropyl.

In one subclass of this class, X is O. In one sub-subclass of thissubclass, R⁴ is hydrogen. In one sub-subclass of this subclass, R⁴ istrifluoromethyl. In one sub-subclass of this subclass, R⁴ iscyclopropyl.

In one subclass of this class, X is NH. In one sub-subclass of thissubclass, R⁴ is hydrogen. In one sub-subclass of this subclass, R⁴ istrifluoromethyl. In one sub-subclass of this subclass, R⁴ iscyclopropyl.

In one subclass of this class, X is S. In one sub-subclass of thissubclass, R⁴ is hydrogen. In one sub-subclass of this subclass, R⁴ istrifluoromethyl. In one sub-subclass of this subclass, R⁴ iscyclopropyl.

In one embodiment, R³ is methyl.

In one class of this embodiment, R² is methyl.

In one subclass of this class, X is O. In one sub-subclass of thissubclass, R⁴ is hydrogen. In one sub-subclass of this subclass, R⁴ istrifluoromethyl. In one sub-subclass of this subclass, R⁴ iscyclopropyl.

In one subclass of this class, X is NH. In one sub-subclass of thissubclass, R⁴ is hydrogen. In one sub-subclass of this subclass, R⁴ istrifluoromethyl. In one sub-subclass of this subclass, R⁴ iscyclopropyl.

In one subclass of this class, X is S. In one sub-subclass of thissubclass, R⁴ is hydrogen. In one sub-subclass of this subclass, R⁴ istrifluoromethyl. In one sub-subclass of this subclass, R⁴ iscyclopropyl.

In one class of this embodiment, R² is cyclopropyl.

In one subclass of this class, X is O. In one sub-subclass of thissubclass, R⁴ is hydrogen. In one sub-subclass of this subclass, R⁴ istrifluoromethyl. In one sub-subclass of this subclass, R⁴ iscyclopropyl.

In one subclass of this class, X is NH. In one sub-subclass of thissubclass, R⁴ is hydrogen. In one sub-subclass of this subclass, R⁴ istrifluoromethyl. In one sub-subclass of this subclass, R⁴ iscyclopropyl.

In one subclass of this class, X is S. In one sub-subclass of thissubclass, R⁴ is hydrogen. In one sub-subclass of this subclass, R⁴ istrifluoromethyl. In one sub-subclass of this subclass, R⁴ iscyclopropyl.

In one embodiment, R³ is

In one class of this embodiment, R² is methyl.

In one subclass of this class, X is O. In one sub-subclass of thissubclass, R⁴ is hydrogen. In one sub-subclass of this subclass, R⁴ istrifluoromethyl. In one sub-subclass of this subclass, R⁴ iscyclopropyl.

In one subclass of this class, X is NH. In one sub-subclass of thissubclass, R⁴ is hydrogen. In one sub-subclass of this subclass, R⁴ istrifluoromethyl. In one sub-subclass of this subclass, R⁴ iscyclopropyl.

In one subclass of this class, X is S. In one sub-subclass of thissubclass, R⁴ is hydrogen. In one sub-subclass of this subclass, R⁴ istrifluoromethyl. In one sub-subclass of this subclass, R⁴ iscyclopropyl.

In one class of this embodiment, R² is cyclopropyl.

In one subclass of this class, X is O. In one sub-subclass of thissubclass, R⁴ is hydrogen. In one sub-subclass of this subclass, R⁴ istrifluoromethyl. In one sub-subclass of this subclass, R⁴ iscyclopropyl.

In one subclass of this class, X is NH. In one sub-subclass of thissubclass, R⁴ is hydrogen. In one sub-subclass of this subclass, R⁴ istrifluoromethyl. In one sub-subclass of this subclass, R⁴ iscyclopropyl.

In one subclass of this class, X is S. In one sub-subclass of thissubclass, R⁴ is hydrogen. In one sub-subclass of this subclass, R⁴ istrifluoromethyl. In one sub-subclass of this subclass, R⁴ iscyclopropyl.

In one embodiment, R³ is

In one class of this embodiment, R² is methyl.

In one subclass of this class, X is O. In one sub-subclass of thissubclass, R⁴ is hydrogen. In one sub-subclass of this subclass, R⁴ istrifluoromethyl. In one sub-subclass of this subclass, R⁴ iscyclopropyl.

In one subclass of this class, X is NH. In one sub-subclass of thissubclass, R⁴ is hydrogen. In one sub-subclass of this subclass, R⁴ istrifluoromethyl. In one sub-subclass of this subclass, R⁴ iscyclopropyl.

In one subclass of this class, X is S. In one sub-subclass of thissubclass, R⁴ is hydrogen. In one sub-subclass of this subclass, R⁴ istrifluoromethyl. In one sub-subclass of this subclass, R⁴ iscyclopropyl.

In one class of this embodiment, R² is cyclopropyl.

In one subclass of this class, X is O. In one sub-subclass of thissubclass, R⁴ is hydrogen. In one sub-subclass of this subclass, R⁴ istrifluoromethyl. In one sub-subclass of this subclass, R⁴ iscyclopropyl.

In one subclass of this class, X is NH. In one sub-subclass of thissubclass, R⁴ is hydrogen. In one sub-subclass of this subclass, R⁴ istrifluoromethyl. In one sub-subclass of this subclass, R⁴ iscyclopropyl.

In one subclass of this class, X is S. In one sub-subclass of thissubclass, R⁴ is hydrogen. In one sub-subclass of this subclass, R⁴ istrifluoromethyl. In one sub-subclass of this subclass, R⁴ iscyclopropyl.

In one embodiment, R³ is

In one class of this embodiment, R² is methyl.

In one subclass of this class, X is O. In one sub-subclass of thissubclass, R⁴ is hydrogen. In one sub-subclass of this subclass, R⁴ istrifluoromethyl. In one sub-subclass of this subclass, R⁴ iscyclopropyl.

In one subclass of this class, X is NH. In one sub-subclass of thissubclass, R⁴ is hydrogen. In one sub-subclass of this subclass, R⁴ istrifluoromethyl. In one sub-subclass of this subclass, R⁴ iscyclopropyl.

In one subclass of this class, X is S. In one sub-subclass of thissubclass, R⁴ is hydrogen. In one sub-subclass of this subclass, R⁴ istrifluoromethyl. In one sub-subclass of this subclass, R⁴ iscyclopropyl.

In one class of this embodiment, R² is cyclopropyl.

In one subclass of this class, X is O. In one sub-subclass of thissubclass, R⁴ is hydrogen. In one sub-subclass of this subclass, R⁴ istrifluoromethyl. In one sub-subclass of this subclass, R⁴ iscyclopropyl.

In one subclass of this class, X is NH. In one sub-subclass of thissubclass, R⁴ is hydrogen. In one sub-subclass of this subclass, R⁴ istrifluoromethyl. In one sub-subclass of this subclass, R⁴ iscyclopropyl.

In one subclass of this class, X is S. In one sub-subclass of thissubclass, R⁴ is hydrogen. In one sub-subclass of this subclass, R⁴ istrifluoromethyl. In one sub-subclass of this subclass, R⁴ iscyclopropyl.

In one embodiment, R³ is

In one class of this embodiment, R² is methyl.

In one subclass of this class, X is O. In one sub-subclass of thissubclass, R⁴ is hydrogen.

In one subclass of this class, X is NH. In one sub-subclass of thissubclass, R⁴ is hydrogen. In one sub-subclass of this subclass, R⁴ istrifluoromethyl. In one sub-subclass of this subclass, R⁴ iscyclopropyl.

In one subclass of this class, X is S. In one sub-subclass of thissubclass, R⁴ is hydrogen. In one sub-subclass of this subclass, R⁴ istrifluoromethyl. In one sub-subclass of this subclass, R⁴ iscyclopropyl.

In one class of this embodiment, R² is cyclopropyl.

In one subclass of this class, X is O. In one sub-subclass of thissubclass, R⁴ is hydrogen. In one sub-subclass of this subclass, R⁴ istrifluoromethyl. In one sub-subclass of this subclass, R⁴ iscyclopropyl.

In one subclass of this class, X is NH. In one sub-subclass of thissubclass, R⁴ is hydrogen. In one sub-subclass of this subclass, R⁴ istrifluoromethyl. In one sub-subclass of this subclass, R⁴ iscyclopropyl.

In one subclass of this class, X is S. In one sub-subclass of thissubclass, R⁴ is hydrogen. In one sub-subclass of this subclass, R⁴ istrifluoromethyl. In one sub-subclass of this subclass, R⁴ iscyclopropyl.

In one embodiment, R² is methyl or cyclopropyl.

In one subclass of this class, X is O. In one sub-subclass of thissubclass, R⁴ is hydrogen. In one sub-subclass of this subclass, R⁴ istrifluoromethyl. In one sub-subclass of this subclass, R⁴ iscyclopropyl.

In one subclass of this class, X is NH. In one sub-subclass of thissubclass, R⁴ is hydrogen. In one sub-subclass of this subclass, R⁴ istrifluoromethyl. In one sub-subclass of this subclass, R⁴ iscyclopropyl.

In one subclass of this class, X is S. In one sub-subclass of thissubclass, R⁴ is hydrogen. In one sub-subclass of this subclass, R⁴ istrifluoromethyl. In one sub-subclass of this subclass, R⁴ iscyclopropyl.

In one embodiment of this invention are compounds of Formula I, whereinthe compounds exist as S and R enantiomers with respect to C*. In oneclass of this embodiment, the compounds of Formula I exist as an Senantiomer with respect to C.

In one class of this embodiment, the compounds of Formula I exist as anR enantiomer with respect to C.

All structural Formulas, embodiments and classes thereof describedherein include the pharmaceutically acceptable salts of the compoundsdefined therein. Reference to the compounds of structural Formula Iincludes the compounds of other generic structural Formulas andembodiments that fall within the scope of Formula I, including but notlimited to Formula Ia to I-d.

“Alkyl”, as well as other groups having the prefix “alk”, such asalkoxy, and the like, means carbon chains which may be linear orbranched, or combinations thereof, containing the indicated number ofcarbon atoms. If no number is specified, 1-6 carbon atoms are intendedfor linear and 3-7 carbon atoms for branched alkyl groups. Examples ofalkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- andtert-butyl, pentyl, hexyl, heptyl, octyl, nonyl and the like.

“Alkoxy” and “alkyl-O—” are used interchangeably and refer to an alkylgroup linked to oxygen.

“Aryl” means phenyl or naphthyl.

“Haloalkyl” include mono-substituted as well as multiple halosubstituted alkyl groups, up to perhalo substituted alkyl. For example,halomethyl, 1,1-difluoroethyl, trifluoromethyl or1,1,1,2,2-pentafluorobutyl are included.

“Cycloalkyl” means a saturated cyclic hydrocarbon radical having thenumber of carbon atoms designated if no number of atoms is specified,3-7 carbon atoms are intended, forming 1-3 carbocyclic rings that arefused. “Cycloalkyl” also includes monocyclic rings fused to an arylgroup in which the point of attachment is on the non-aromatic portion.Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, tetrahydronaphthyl, decahydronaphthyl, indanyland the like.

“Heterocyclyl” “heterocycle” or “heterocyclic” refers to nonaromaticcyclic ring structures in which one or more atoms in the ring, theheteroatom(s), is an element other than carbon. Heterocyclyl groups canhave one or more unsaturated bonds. Heteroatoms are typically O, S or Natoms. Examples of heterocyclyl groups include: piperidine, piperazinyl,morpholinyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl, oxiranyl, oraziridinyl, and the like.

“Heteroaryl” refers to aromatic cyclic ring structures in which one ormore atoms in the ring, the heteroatoms(s), is an element other thancarbon. Heteroatoms are typically O, S, or N atoms. Examples ofheteroaromatic groups include: pyridinyl, pyrimidinyl, pyrrolyl,pyridazinyl, isoxazolyl, indolyl, or imidazolyl.

“Halogen” (or “halo”) unless otherwise indicated, includes fluorine(fluoro), chlorine (chloro), bromine (bromo) and iodine (iodo). In oneembodiment, halo is fluoro (—F) or chloro (—Cl).

When any variable (e.g., R¹, R², etc.) occurs more than one time in anyconstituent or in Formula I or other generic Formulae herein, itsdefinition on each occurrence is independent of its definition at everyother occurrence. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds. Inchoosing compounds of the present invention, one of ordinary skill inthe art will recognize that the various substituents, i.e., R¹, R²,etc., are to be chosen in conformity with well-known principles ofchemical structure connectivity and stability. Unless expressly statedto the contrary, substitution by a named substituent is permitted on anyatom in a ring (e.g., aryl, a heteroaryl ring, or a saturatedheterocyclic ring) provided such ring substitution is chemically allowedand results in a stable compound. A “stable” compound is a compoundwhich can be prepared and isolated and whose structure and propertiesremain or can be caused to remain essentially unchanged for a period oftime sufficient to allow use of the compound for the purposes describedherein (e.g., therapeutic or prophylactic administration to a subject).

The term “substituted” shall be deemed to include multiple degrees ofsubstitution by a named substituent. Where multiple substituent moietiesare disclosed or claimed, the substituted compound can be independentlysubstituted by one or more of the disclosed or claimed substituentmoieties, singly or plurally. By independently substituted, it is meantthat the (two or more) substituents can be the same or different.

Unless expressly depicted or described otherwise, variables depicted ina structural formula with a “floating” bond are permitted on anyavailable carbon atom in the ring to which the variable is attached.When a moiety is noted as being “optionally substituted” in Formula I orany embodiment thereof, it means that Formula I or the embodimentthereof encompasses compounds that contain the noted substituent (orsubstituents) on the moiety and also compounds that do not contain thenoted substituent (or substituents) on the moiety.

Compounds of structural Formulas I may contain one or more asymmetriccenters and can thus occur as racemates and racemic mixtures, singleenantiomers, diastereoisomeric mixtures and individual diastereoisomers.Centers of asymmetry that are present in the compounds of Formula I canall independently of one another have S configuration or Rconfiguration. The compounds of this invention include all possibleenantiomers and diastereomers and mixtures of two or more stereoisomers,for example mixtures of enantiomers and/or diastereomers, in all ratios.Thus, enantiomers are a subject of the invention in enantiomericallypure form, both as levorotatory and as dextrorotatory antipodes, in theform of racemates and in the form of mixtures of the two enantiomers inall ratios. In the case of a cis/trans isomerism the invention includesboth the cis form and the trans form as well as mixtures of these formsin all ratios. The present invention is meant to comprehend all suchstereo-isomeric forms of the compounds of structural Formula I.

Compounds of structural Formula I may be separated into their individualdiastereoisomers by, for example, fractional crystallization from asuitable solvent, for example methanol or ethyl acetate or a mixturethereof, or via chiral chromatography using an optically activestationary phase. Absolute stereochemistry may be determined by X-raycrystallography of crystalline products or crystalline intermediateswhich are derivatized, if necessary, with a reagent containing anasymmetric center of known absolute configuration. Alternatively, anystereoisomer or isomers of a compound of Formula I may be obtained bystereospecific synthesis using optically pure starting materials orreagents of known absolute configuration.

If desired, racemic mixtures of the compounds may be separated so thatthe individual enantiomers are isolated. The separation can be carriedout by methods well known in the art, such as the coupling of a racemicmixture of compounds to an enantiomerically pure compound to form adiastereoisomeric mixture, followed by separation of the individualdiastereoisomers by standard methods, such as fractional crystallizationor chromatography. The coupling reaction is often the formation of saltsusing an enantiomerically pure acid or base. The diasteromericderivatives may then be converted to the pure enantiomers by cleavage ofthe added chiral residue. The racemic mixture of the compounds can alsobe separated directly by chromatographic methods utilizing chiralstationary phases, which methods are well known in the art.

For compounds of Formula I described herein which contain olefinicdouble bonds, unless specified otherwise, they are meant to include bothE and Z geometric isomers.

Some of the compounds described herein may exist as tautomers which havedifferent points of attachment of hydrogen accompanied by one or moredouble bond shifts. For example, a ketone and its enol form areketo-enol tautomers. The individual tautomers as well as mixturesthereof are encompassed with compounds of Formula I of the presentinvention.

In the compounds of structural Formula I, the atoms may exhibit theirnatural isotopic abundances, or one or more of the atoms may beartificially enriched in a particular isotope having the same atomicnumber, but an atomic mass or mass number different from the atomic massor mass number predominantly found in nature. The present invention asdescribed and claimed herein is meant to include all suitable isotopicvariations of the compounds of structural Formula I and embodimentsthereof. For example, different isotopic forms of hydrogen (H) includeprotium (¹H) and deuterium (²H, also denoted herein as D). Protium isthe predominant hydrogen isotope found in nature. Enriching fordeuterium may afford certain therapeutic advantages, such as increasingin vivo half-life or reducing dosage requirements, or may provide acompound useful as a standard for characterization of biologicalsamples. Isotopically-enriched compounds within structural Formula I,can be prepared without undue experimentation by conventional techniqueswell known to those skilled in the art or by processes analogous tothose described in the Schemes and Examples herein using appropriateisotopically-enriched reagents and/or intermediates.

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids. When thecompound of the present invention is acidic, its corresponding salt canbe conveniently prepared from pharmaceutically acceptable non-toxicbases, including inorganic bases and organic bases. Salts derived fromsuch inorganic bases include aluminum, ammonium, calcium, copper (ic andous), ferric, ferrous, lithium, magnesium, manganese (ic and ous),potassium, sodium, zinc and the like salts. Preferred are the ammonium,calcium, magnesium, potassium and sodium salts. Salts prepared frompharmaceutically acceptable organic non-toxic bases include salts ofprimary, secondary, and tertiary amines derived from both naturallyoccurring and synthetic sources. Pharmaceutically acceptable organicnon-toxic bases from which salts can be formed include, for example,arginine, betaine, caffeine, choline, N,N′-dibenzylethylenediamine,diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol,ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine,glucamine, glucosamine, histidine, hydrabamine, isopropylamine,dicyclohexylamine, lysine, methylglucamine, morpholine, piperazine,piperidine, polyamine resins, procaine, purines, theobromine,triethylamine, trimethylamine, tripropylamine, tromethamine and thelike.

When the compound of the present invention is basic, its correspondingsalt can be conveniently prepared from pharmaceutically acceptablenon-toxic inorganic and organic acids. Such acids include, for example,acetic, benzenesulfonic, benzoic, camphorsulfonic, citric,ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric,isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic,nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric,p-toluenesulfonic acid and the like. Preferred are citric, hydrobromic,hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids. If thecompounds of Formula I simultaneously contain acidic and basic groups inthe molecule the invention also includes, in addition to the salt formsmentioned, inner salts or betaines (zwitterions). Salts can be obtainedfrom the compounds of Formula I by customary methods which are known tothe person skilled in the art, for example by combination with anorganic or inorganic acid or base in a solvent or dispersant, or byanion exchange or cation exchange from other salts. The presentinvention also includes all salts of the compounds of Formula I which,owing to low physiological compatibility, are not directly suitable foruse in pharmaceuticals but which can be used, for example, asintermediates for chemical reactions or for the preparation ofpharmaceutically acceptable salts.

Furthermore, compounds of the present invention may exist in amorphousform and/or one or more crystalline forms, and as such all amorphous andcrystalline forms and mixtures thereof of the compounds of Formula I,including the Examples, are intended to be included within the scope ofthe present invention. In addition, some of the compounds of the instantinvention may form solvates with water (i.e., a hydrate) or commonorganic solvents such as but not limited to ethyl acetate. Such solvatesand hydrates, particularly the pharmaceutically acceptable solvates andhydrates, of the instant compounds are likewise encompassed within thescope of this invention, along with un-solvated and anhydrous forms.

Any pharmaceutically acceptable pro-drug modification of a compound ofthis invention which results in conversion in vivo to a compound withinthe scope of this invention is also within the scope of this invention.For example, esters can optionally be made by esterification of anavailable carboxylic acid (—COOH) group or by formation of an ester onan available hydroxy group in a compound. Similarly, labile amides canbe made. Pharmaceutically acceptable esters or amides of the compoundsof this invention may be prepared to act as pro-drugs which can behydrolyzed back to an acid (or —COO— depending on the pH of the fluid ortissue where conversion takes place) or hydroxy form particularly invivo and as such are encompassed within the scope of this invention.Included are those esters and acyl groups known in the art for modifyingthe solubility or hydrolysis characteristics for use assustained-release or prodrug formulations. Also, in the case of acarboxylic acid (—COOH) or alcohol group being present in the compoundsof the present invention, pharmaceutically acceptable esters ofcarboxylic acid derivatives, such as methyl, ethyl, orpivaloyloxymethyl, or acyl derivatives of alcohols, such as O-acetyl,O-pivaloyl, O-benzoyl, and O-aminoacyl, can be employed.

The present invention also relates to processes for the preparation ofthe compounds of Formula I which are described in the following and bywhich the compounds of the invention are obtainable.

The compounds of Formula I according to the invention effect an increaseof cGMP concentration via the activation of the soluble guanylatecyclase (sGC), and they are therefore useful agents for the therapy andprophylaxis of disorders which are associated with a low or decreasedcGMP level or which are caused thereby, or for whose therapy orprophylaxis an increase of the present cGMP level is desired. Theactivation of the sGC by the compounds of Formula I can be examined, forexample, in the activity assay described below.

The terms “therapeutically effective (or efficacious) amount” andsimilar descriptions such as “an amount efficacious for treatment” areintended to mean that amount of a pharmaceutical drug that will elicitthe biological or medical response of a tissue, a system, animal orhuman that is being sought by a researcher, veterinarian, medical doctoror other clinician. The terms “prophylactically effective (orefficacious) amount” and similar descriptions such as “an amountefficacious for prevention” are intended to mean that amount of apharmaceutical drug that will prevent or reduce the risk of occurrenceof the biological or medical event that is sought to be prevented in atissue, a system, animal or human by a researcher, veterinarian, medicaldoctor or other clinician. As an example, the dosage a patient receivescan be selected so as to achieve the desired reduction in bloodpressure; the dosage a patient receives may also be titrated over timein order to reach a target blood pressure. The dosage regimen utilizinga compound of the instant invention is selected in accordance with avariety of factors including type, species, age, weight, sex and medicalcondition of the patient; the severity of the condition to be treated;the potency of the compound chosen to be administered; the route ofadministration; and the renal and hepatic function of the patient. Aconsideration of these factors is well within the purview of theordinarily skilled clinician for the purpose of determining thetherapeutically effective or prophylactically effective dosage amountneeded to prevent, counter, or arrest the progress of the condition. Itis understood that a specific daily dosage amount can simultaneously beboth a therapeutically effective amount, e.g., for treatment ofhypertension, and a prophylactically effective amount, e.g., forprevention of myocardial infarction.

Disorders and pathological conditions which are associated with a lowcGMP level or in which an increase of the cGMP level is desired and forwhose therapy and prophylaxis it is possible to use compounds of FormulaI are, for example, cardiovascular diseases, such as endothelialdysfunction, diastolic dysfunction, atherosclerosis, hypertension, heartfailure, pulmonary hypertension, which includes pulmonary arterialhypertension (PAH), stable and unstable angina pectoris, thromboses,restenoses, myocardial infarction, strokes, cardiac insufficiency,fibrosis or pulmonary hypertonia, or, for example, erectile dysfunction,asthma bronchiale, chronic kidney insufficiency and diabetes. Compoundsof Formula I can additionally be used in the therapy of cirrhosis of theliver and also for improving a restricted memory performance or abilityto learn.

The compounds of Formula I and their pharmaceutically acceptable saltscan be administered to animals, preferably to mammals, and in particularto humans, as pharmaceuticals by themselves, in mixtures with oneanother or in the form of pharmaceutical compositions. The term“patient” includes animals, preferably mammals and especially humans,who use the instant active agents for the prevention or treatment of amedical condition. Administering of the drug to the patient includesboth self-administration and administration to the patient by anotherperson. The patient may be in need of, or desire, treatment for anexisting disease or medical condition, or may be in need of or desireprophylactic treatment to prevent or reduce the risk of occurrence ofsaid disease or medical condition. As used herein, a patient “in need”of treatment of an existing condition or of prophylactic treatmentencompasses both a determination of need by a medical professional aswell as the desire of a patient for such treatment.

A subject of the present invention therefore also are the compounds ofFormula I and their pharmaceutically acceptable salts for use aspharmaceuticals, their use for activating soluble guanylate cyclase, fornormalizing a disturbed cGMP balance and in particular their use in thetherapy and prophylaxis of the abovementioned syndromes as well as theiruse for preparing medicaments for these purposes.

Furthermore, a subject of the present invention are pharmaceuticalcompositions which comprise as active component an effective dose of atleast one compound of

Formula I and/or a pharmaceutically acceptable salt thereof and acustomary pharmaceutically acceptable carrier, i.e., one or morepharmaceutically acceptable carrier substances and/or additives.

Thus, a subject of the invention are, for example, said compound and itspharmaceutically acceptable salts for use as a pharmaceutical,pharmaceutical compositions which comprise as active component aneffective dose of said compound and/or a pharmaceutically acceptablesalt thereof and a customary pharmaceutically acceptable carrier, andthe uses of said compound and/or a pharmaceutically acceptable saltthereof in the therapy or prophylaxis of the abovementioned syndromes aswell as their use for preparing medicaments for these purposes.

The pharmaceutical compositions according to the invention can beadministered orally, for example in the form of pills, tablets,lacquered tablets, sugar-coated tablets, granules, hard and soft gelatincapsules, aqueous, alcoholic or oily solutions, syrups, emulsions orsuspensions, or rectally, for example in the form of suppositories.Administration can also be carried out parenterally, for examplesubcutaneously, intramuscularly or intravenously in the form ofsolutions for injection or infusion. Other suitable administration formsare, for example, percutaneous or topical administration, for example inthe form of ointments, tinctures, sprays or transdermal therapeuticsystems, or the inhalative administration in the form of nasal sprays oraerosol mixtures, or, for example, microcapsules, implants or rods. Thepreferred administration form depends, for example, on the disease to betreated and on its severity.

The amount of active compound of Formula I and/or its pharmaceuticallyacceptable salts in the pharmaceutical composition normally is from 0.1to 200 mg, preferably from 1 to 200 mg, per dose, but depending on thetype of the pharmaceutical composition it can also be higher. Thepharmaceutical compositions usually comprise 0.5 to 90 percent by weightof the compounds of Formula I and/or their pharmaceutically acceptablesalts. The preparation of the pharmaceutical compositions can be carriedout in a manner known per se. For this purpose, one or more compounds ofFormula I and/or their pharmaceutically acceptable salts, together withone or more solid or liquid pharmaceutical carrier substances and/oradditives (or auxiliary substances) and, if desired, in combination withother pharmaceutically active compounds having therapeutic orprophylactic action, are brought into a suitable administration form ordosage form which can then be used as a pharmaceutical in human orveterinary medicine.

For the production of pills, tablets, sugar-coated tablets and hardgelatin capsules, it is possible to use, for example, lactose, starch,for example maize starch, or starch derivatives, talc, stearic acid orits salts, etc. Carriers for soft gelatin capsules and suppositoriesare, for example, fats, waxes, semisolid and liquid polyols, natural orhardened oils, etc. Suitable carriers for the preparation of solutions,for example of solutions for injection, or of emulsions or syrups are,for example, water, physiologically sodium chloride solution, alcoholssuch as ethanol, glycerol, polyols, sucrose, invert sugar, glucose,mannitol, vegetable oils, etc. It is also possible to lyophilize thecompounds of Formulas I and their pharmaceutically acceptable salts andto use the resulting lyophilisates, for example, for preparingpreparations for injection or infusion. Suitable carriers formicrocapsules, implants or rods are, for example, copolymers of glycolicacid and lactic acid.

Besides the active compounds and carriers, the pharmaceuticalcompositions can also contain customary additives, for example fillers,disintegrants, binders, lubricants, wetting agents, stabilizers,emulsifiers, dispersants, preservatives, sweeteners, colorants,flavorings, aromatizers, thickeners, diluents, buffer substances,solvents, solubilizers, agents for achieving a depot effect, salts foraltering the osmotic pressure, coating agents or antioxidants.

The dosage of the active compound of Formula I and/or of apharmaceutically acceptable salt thereof to be administered depends onthe individual case and is, as is customary, to be adapted to theindividual circumstances to achieve an optimum effect. Thus, it dependson the nature and the severity of the disorder to be treated, and alsoon the sex, age, weight and individual responsiveness of the human oranimal to be treated, on the efficacy and duration of action of thecompounds used, on whether the therapy is acute or chronic orprophylactic, or on whether other active compounds are administered inaddition to compounds of Formula I. In general, a daily dose ofapproximately 0.01 to 100 mg/kg, preferably 0.01 to 10 mg/kg, inparticular 0.3 to 5 mg/kg (in each case mg per kg of body weight) isappropriate for administration to an adult weighing approximately 75 kgin order to obtain the desired results. The daily dose can beadministered in a single dose or, in particular when larger amounts areadministered, be divided into several, for example two, three or fourindividual doses. In some cases, depending on the individual response,it may be necessary to deviate upwards or downwards from the given dailydose. A single daily dose is preferred.

The compounds of Formula I activate soluble guanylate cyclase. Onaccount of this property, apart from use as pharmaceutically activecompounds in human medicine and veterinary medicine, they can also beemployed as a scientific tool or as an aid for biochemicalinvestigations in which such an effect on soluble guanylate cyclase isintended, and also for diagnostic purposes, for example in the in vitrodiagnosis of cell samples or tissue samples. The compounds of Formula Iand salts thereof can furthermore be employed, as already mentionedabove, as intermediates for the preparation of other pharmaceuticallyactive compounds.

One or more additional pharmacologically active agents may beadministered in combination with a compound of Formula I. An additionalactive agent (or agents) is intended to mean a pharmaceutically activeagent (or agents) that is active in the body, including pro-drugs thatconvert to pharmaceutically active form after administration, which aredifferent from the compound of Formula I, and also includes free-acid,free-base and pharmaceutically acceptable salts of said additionalactive agents. Generally, any suitable additional active agent oragents, including but not limited to anti-hypertensive agents,anti-atherosclerotic agents such as a lipid modifying compound,anti-diabetic agents and/or anti-obesity agents may be used in anycombination with the compound of Formula I in a single dosageformulation (a fixed dose drug combination), or may be administered tothe patient in one or more separate dosage formulations which allows forconcurrent or sequential administration of the active agents(co-administration of the separate active agents). Examples ofadditional active agents which may be employed include but are notlimited to angiotensin converting enzyme inhibitors (e.g. alacepril,benazepril, captopril, ceronapril, cilazapril, delapril, enalapril,enalaprilat, fosinopril, imidapril, lisinopril, moveltipril,perindopril, quinapril, ramipril, spirapril, temocapril, ortrandolapril), angiotensin II receptor antagonists (e.g., losartan i.e.,COZAAR®, valsartan, candesartan, olmesartan, telmesartan and any ofthese drugs used in combination with hydrochlorothiazide such asHYZAAR®); neutral endopeptidase inhibitors (e.g., thiorphan andphosphoramidon), aldosterone antagonists, aldosterone synthaseinhibitors, renin inhibitors (e.g. urea derivatives of di- andtri-peptides (See U.S. Pat. No. 5,116,835), amino acids and derivatives(U.S. Pat. Nos. 5,095,119 and 5,104,869), amino acid chains linked bynon-peptidic bonds (U.S. Pat. No. 5,114,937), di- and tri-peptidederivatives (U.S. Pat. No. 5,106,835), peptidyl amino diols (U.S. Pat.Nos. 5,063,208 and 4,845,079) and peptidyl beta-aminoacyl aminodiolcarbamates (U.S. Pat. No. 5,089,471); also, a variety of other peptideanalogs as disclosed in the following U.S. Pat. Nos. 5,071,837;5,064,965; 5,063,207; 5,036,054; 5,036,053; 5,034,512 and 4,894,437, andsmall molecule renin inhibitors (including diol sulfonamides andsulfinyls (U.S. Pat. No. 5,098,924), N-morpholino derivatives (U.S. Pat.No. 5,055,466), N-heterocyclic alcohols (U.S. Pat. No. 4,885,292) andpyrolimidazolones (U.S. Pat. No. 5,075,451); also, pepstatin derivatives(U.S. Pat. No. 4,980,283) and fluoro- and chloro-derivatives ofstatone-containing peptides (U.S. Pat. No. 5,066,643), enalkrein, RO42-5892, A 65317, CP 80794, ES 1005, ES 8891, SQ 34017, aliskiren(2(S),4(S),5(S),7(S)—N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)-phenyl]-octanamidhemifumarate) SPP600, SPP630 and SPP635), endothelin receptorantagonists, phosphodiesterase-5 inhibitors (e.g. sildenafil, tadalfiland vardenafil), vasodilators, calcium channel blockers (e.g.,amlodipine, nifedipine, veraparmil, diltiazem, gallopamil, niludipine,nimodipins, nicardipine), potassium channel activators (e.g.,nicorandil, pinacidil, cromakalim, minoxidil, aprilkalim, loprazolam),diuretics (e.g., hydrochlorothiazide), sympatholitics, beta-adrenergicblocking drugs (e.g., propranolol, atenolol, bisoprolol, carvedilol,metoprolol, or metoprolol tartate), alpha adrenergic blocking drugs(e.g., doxazocin, prazocin or alpha methyldopa) central alpha adrenergicagonists, peripheral vasodilators (e.g. hydralazine); lipid loweringagents e.g., HMG-CoA reductase inhibitors such as simvastatin andlovastatin which are marketed as ZOCOR® and MEVACOR® in lactone pro-drugform and function as inhibitors after administration, andpharmaceutically acceptable salts of dihydroxy open ring acid HMG-CoAreductase inhibitors such as atorvastatin (particularly the calcium saltsold in LIPITOR®), rosuvastatin (particularly the calcium salt sold inCRESTOR®), pravastatin (particularly the sodium salt sold inPRAVACHOL®), and fluvastatin (particularly the sodium salt sold inLESCOL®); a cholesterol absorption inhibitor such as ezetimibe (ZETIA®)and ezetimibe in combination with any other lipid lowering agents suchas the HMG-CoA reductase inhibitors noted above and particularly withsimvastatin (VYTORIN®) or with atorvastatin calcium; niacin inimmediate-release or controlled release forms, and/or with an HMG-CoAreductase inhibitor; niacin receptor agonists such as acipimox andacifran, as well as niacin receptor partial agonists; metabolic alteringagents including insulin and insulin mimetics (e.g., insulin degludec,insulin glargine, insulin lispro), dipeptidyl peptidase-IV (DPP-4)inhibitors (e.g., sitagliptin, alogliptin, omarigliptin, linagliptin,vildagliptin); insulin sensitizers, including (i) PPARγ agonists, suchas the glitazones (e.g. pioglitazone, AMG 131, MBX2044, mitoglitazone,lobeglitazone, IDR-105, rosiglitazone, and balaglitazone), and otherPPAR ligands, including (1) PPARα/γ dual agonists (e.g., ZYH2, ZYH1,GFT505, chiglitazar, muraglitazar, aleglitazar, sodelglitazar, andnaveglitazar); (2) PPARα agonists such as fenofibric acid derivatives(e.g., gemfibrozil, clofibrate, ciprofibrate, fenofibrate, bezafibrate),(3) selective PPARγ modulators (SPPARγM's), (e.g., such as thosedisclosed in WO 02/060388, WO 02/08188, WO 2004/019869, WO 2004/020409,WO 2004/020408, and WO 2004/066963); and (4) PPARγ partial agonists;(ii) biguanides, such as metformin and its pharmaceutically acceptablesalts, in particular, metformin hydrochloride, and extended-releaseformulations thereof, such as Glumetza™, Fortamet™, and GlucophageXR™;and (iii) protein tyrosine phosphatase-1B (PTP-1B) inhibitors (e.g.,ISIS-113715 and TTP814); insulin or insulin analogs (e.g., insulindetemir, insulin glulisine, insulin degludec, insulin glargine, insulinlispro and inhalable formulations of each); leptin and leptinderivatives and agonists; amylin and amylin analogs (e.g., pramlintide);sulfonylurea and non-sulfonylurea insulin secretagogues (e.g.,tolbutamide, glyburide, glipizide, glimepiride, mitiglinide,meglitinides, nateglinide and repaglinide); α-glucosidase inhibitors(e.g., acarbose, voglibose and miglitol); glucagon receptor antagonists(e.g., MK-3577, MK-0893, LY-2409021 and KT6-971); incretin mimetics,such as GLP-1, GLP-1 analogs, derivatives, and mimetics; and GLP-1receptor agonists (e.g., dulaglutide, semaglutide, albiglutide,exenatide, liraglutide, lixisenatide, taspoglutide, CJC-1131, andBIM-51077, including intranasal, transdermal, and once-weeklyformulations thereof); LDL cholesterol lowering agents such as (i)HMG-CoA reductase inhibitors (e.g., simvastatin, lovastatin,pravastatin, cerivastatin, fluvastatin, atorvastatin, and rosuvastatin),(ii) bile acid sequestering agents (e.g., colestilan, colestimide,colesevalam hydrochloride, colestipol, cholestyramine, anddialkylaminoalkyl derivatives of a cross-linked dextran), (iii)inhibitors of cholesterol absorption, (e.g., ezetimibe), and (iv) acylCoA:cholesterol acyltransferase inhibitors, (e.g., avasimibe);HDL-raising drugs, (e.g., niacin and nicotinic acid receptor agonists,and extended-release versions thereof; antiobesity compounds; agentsintended for use in inflammatory conditions, such as aspirin,non-steroidal anti-inflammatory drugs or NSAIDs, glucocorticoids, andselective cyclooxygenase-2 or COX-2 inhibitors; glucokinase activators(GKAs) (e.g., AZD6370); inhibitors of 11β-hydroxysteroid dehydrogenasetype 1, (e.g., such as those disclosed in U.S. Pat. No. 6,730,690, andLY-2523199); CETP inhibitors (e.g., anacetrapib, and torcetrapib);inhibitors of fructose 1,6-bisphosphatase, (e.g., such as thosedisclosed in U.S. Pat. Nos. 6,054,587; 6,110,903; 6,284,748; 6,399,782;and 6,489,476); inhibitors of acetyl CoA carboxylase-1 or 2 (ACC1 orACC2); AMP-activated Protein Kinase (AMPK) activators; other agonists ofthe G-protein-coupled receptors: (i) GPR-109, (ii) GPR-119 (e.g.,MBX2982 and PSN821), and (iii) GPR-40; SSTR3 antagonists (e.g., such asthose disclosed in WO 2009/001836); neuromedin U receptor agonists(e.g., such as those disclosed in WO 2009/042053, including, but notlimited to, neuromedin S (NMS)); SCD modulators; GPR-105 antagonists(e.g., such as those disclosed in WO 2009/000087); SGLT inhibitors(e.g., ASP1941, SGLT-3, empagliflozin, dapagliflozin, canagliflozin,BI-10773, ertugliflozin, remogloflozin, TS-071, tofogliflozin,ipragliflozin, and LX-4211); inhibitors of acyl coenzymeA:diacylglycerol acyltransferase 1 and 2 (DGAT-1 and DGAT-2); inhibitorsof fatty acid synthase; inhibitors of acyl coenzyme A:monoacylglycerolacyltransferase 1 and 2 (MGAT-1 and MGAT-2); agonists of the TGR5receptor (also known as GPBAR1, BG37, GPCR19, GPR131, and M-BAR); ilealbile acid transporter inhibitors; PACAP, PACAP mimetics, and PACAPreceptor 3 agonists; PPAR agonists; protein tyrosine phosphatase-1B(PTP-1B) inhibitors; IL-1b antibodies, (e.g., XOMA052 and canakinumab);and bromocriptine mesylate and rapid-release formulations thereof; orwith other drugs beneficial for the prevention or the treatment of theabove-mentioned diseases including nitroprusside and diazoxide thefree-acid, free-base, and pharmaceutically acceptable salt forms of theabove active agents where chemically possible.

The following examples are provided so that the invention might be morefully understood. Unless otherwise indicated, the starting materials arecommercially available. They should not be construed as limiting theinvention in any way.

Several methods for preparing the compounds of this invention aredescribed in the following Schemes and Examples. Starting materials andintermediates are purchased, made from known procedures, or as otherwiseillustrated. Some frequently applied routes to the compounds of FormulaI are also described by the Schemes as follows. In some cases the orderof carrying out the steps of reaction schemes may be varied tofacilitate the reaction or to avoid unwanted reaction products. The “R”and “X” groups in the Schemes correspond to the variables defined inFormula I at the same positions on the structures.

Compounds of Formula S-I can be prepared from the nitrile precursor(S-1a) as outlined in Scheme 1. Conversion of the imidazo[1,2-a]pyrazinenitrile S-1a to the amidine intermediate S-1b can be accomplished with areagent such as amino(chloro)methylaluminum, prepared fromtrimethylaluminum and NH₄Cl, in a non-polar solvent such as toluene atelevated temperature as described by Garigipati, R. S. et al TetrahedronLetters 1990, 31(14), 1969. The nitrile S-1a can also be converted tothe amidine S-1b by using sodium methoxide in methanol to form theimidate which can then be transformed to the amidine S-1b using NH₄Cland AcOH as described by Pinner, A. et al, Ber. Dtsch. Chem. Ges. 1877,10, 1889. Treatment of the amidine S-1b with a suitable malononitrileintermediate S-1c in an alcoholic solvent such as t-BuOH, EtOH, or MeOH,in the presence of a suitable base such as NaHCO₃, KHCO₃, or Na₂CO₃ atelevated temperature provides compounds with Formula S-I. The reactionsin Scheme 1 may also be carried out on the corresponding ester ofcompound S-1a, and corresponding methyl, ethyl, or propyl esters ofcompound S-1C.

The nitrile intermediate S-1a can be prepared from commerciallyavailable 3,5-dibromopyrazin-2-amine (S-2a) as depicted in Scheme 2.3,5-Dibromopyrazin-2-amine (2a) can be treated with a suitablealpha-haloketone reagent (S-2b) to afford the dibromo intermediate S-2c.The dibromo intermediate S-2c can be selectively displaced with analcohol, amine, or sulfide in the presence of a base such as Na₂CO₃,Cs₂CO₃, NaH, or DIEA to give compound S-2d, which can be transformedinto the nitrile intermediate S-1a using Zn(CN)₂ and a palladiumcatalyst such as Pd(dppf)Cl₂ at an elevated temperature.

Alternatively, compounds of Formula I can be prepared as depicted inScheme 3. The dibromo intermediate (S-2c) from Scheme 2 can be convertedto the thiomethyl intermediate (S-3a) by nucleophilic displacement usingsodium thiomethoxide as described by Belanger, D. B. et al Bioorg. Med.Chem. Lett. 2010, 20, 5170. Compound S-3b can be obtained by treatmentof the intermediate 3a with a reagent such as Zn(CN)₂ in the presence ofa suitable palladium catalyst such as Pd(dppf)Cl₂. The nitrileintermediate (S-3b) can be transformed to the amidine intermediate(S-3c) and subsequently cyclized with a suitable malononitrile reagent(S-1c) to afford the thiomethyl intermediate (S-3d) as similarlydescribed in Scheme 1. Treatment of intermediate S-3d with an oxidant,such as Oxone® or m-CPBA in the presence of an acid such as sulfuricacid, can generate intermediate S-3e. Intermediate S-3e can be displacedwith a suitable alcohol, amine, or thiol using a base such as Na₂CO₃,Cs₂CO₃, NaH, or Hunig's base. This transformation can also occur underneutral conditions upon microwave irradiation or thermal heating toafford compounds of Formula S-I.

The preparation of compound 1c is outlined in Scheme 4. Deprotonation ofester S-4a using a suitable base such as LiHMDS, NaHMDS, NaH or LDA in asolvent such as THF or DMF followed by treatment with an alkyl iodideaffords the intermediate S-4b. Treatment of intermediate S-4b with asuitable brominating reagent such as NBS and AIBN in a solvent such ascarbon tetrachloride at refluxing temperatures affords intermediateS-4c. Intermediate S-4c can be transformed to compound S-1c by reactionwith malononitrile in the presence of a suitable base such as NaH,t-BuOK, K₂CO₃ or DBU in a solvent such as THF or DMF at RT or atelevated temperature. The synthetic sequence depicted in Scheme 4 canalso be similarly used to prepare the corresponding ethyl or propylesters of compound S-1c.

The ester (S-4a) can be prepared from the corresponding carboxylic acidby one skilled in the art. The ester (S-4a) may also be prepared by theα-arylation/heteroarylation of esters as described by Buchwald, S. L. etal Organic Letters 2009, 11(8), 1773; or by Shen, H. C. et al OrganicLetters 2006, 8(7), 1447. Commercially available aryl bromides can beconverted to compound S-4a (depicted as the ethyl ester) by the reactionwith diethyl malonate in the presence of a suitable catalyst system suchas CuI and picolinic acid, followed by decarboxylation at elevatedtemperature according to Scheme 5.

In addition to the method described in Scheme 4, intermediates S-1c,depicted as the ethyl ester, may also be prepared as shown in Scheme 6.Thus, treatment of diethyl oxalate with a suitable aryl magnesiumbromide (with or without lithium chloride additive) or the lithiate ofheteroaryl reagents derived via metal-halogen exchange in a suitablesolvent such as THF affords compound S-6b. Treatment of compound S-6bwith malononitrile and a suitable base such as piperidine in a solventsuch as EtOH at elevated temperature affords compound S-6c. CompoundS-6c, upon treatment with a suitable alkyl magnesium bromide (with orwithout lithium chloride additive) in a solvent such as THF affordscompound S-1c.

Compounds of the present invention possess an asymmetric center at thecarbon bearing the R²/R³ substituent which can be either R or Sconfiguration. These enantiomeric mixtures may be separated or resolvedto single enantiomers using methods familiar to those skilled in theart. For example, compounds of the present invention may be resolved tothe pure isomers by using chiral SFC chromatography. Racemic materialcan be resolved to enantiomerically pure compounds whenever possible andat any step in the route. Characterization data may be of the chiral orracemic material.

The independent synthesis of diastereomers and enantiomers or theirchromatographic separations may be achieved as known in the art byappropriate modification of the methodology disclosed herein. Theirabsolute stereochemistry may be determined by X-ray crystallography ofcrystalline products or crystalline intermediates which are derivatized,if necessary, with a reagent containing an asymmetric center of knownabsolute stereochemistry, or by vibrational circular dichroism (VCD)spectroscopy.

Throughout the synthetic schemes and examples, abbreviations andacronyms may be used with the following meanings unless otherwiseindicated: aq, aq.=aqueous; Ac=acetate; ACN=acetonitrile;AIBN=azobisisobutyronitrile; anhyd.=anhydrous; Ar=aryl; br s=broadsinglet; Bu=butyl, t-Bu=tert-butyl; Bn=benzyl; t-BuONO=tert-butylnitrite; t-BuOH=tert butanol; t-BuOK=potassium tert-butoxide; °C.=degree; CELITE=diatomaceous earth; Celsius; CD₃CN=deuteratedacetonitrile; CD₃OD=deuterated methanol; cPr, cyPr=cyclopropyl; conc,conc.=concentrated; DBU=1,8-diazobicyclo[5.4.0]undec-7-ene;dppf=1,1′-Bis(diphenylphosphino)ferrocene; DCM=dichloromethane;DCE=1,2-dichloroethane; DME=1,2-dimethoxyethane;DIEA=N,N-diisopropylethylamine; DMF=N,N-dimethylformamide; DMA,DMAC=dimethylacetamide; DMSO=dimethylsulfoxide; Et=ethyl;eq.=equivalent(s); EtOAc=ethyl acetate; EtOH=ethanol; h, hr=hour;HPLC=High pressure liquid chromatography; iPr=isopropyl; iPA, IPA,i-PrOH=isopropyl alcohol; LDA=lithium diisopropylamide; LiHMDS=lithiumbis(trimethylsilyl)amide; Me=methyl; MeOH=methanol; mg=milligram; min,min.=minute; mL=milliliter; Mp=melting point;mCPBA=3-chloroperoxybenzoic acid; min.=minute; mmol is millimoles;NaHMDS=sodium bis(trimethylsilyl)amide; NBS=N-bromosuccinimide;NMP=N-methylpyrrolidone; PE=petroleum ether; PDA=photodiode array;NMR=nuclear magnetic resonance; oxone®=potassium peroxymonosulfate;Pr=propyl; Ph=phenyl; rt=retention time; psig=pounds per square inchgauge; RT=room temperature; sat., satd=saturated; SFC=supercriticalfluid chromatography; TEA=triethylamine; TFA=trifluoroacetic acid;THF=tetrahydrofuran; TLC=thin layer chromatography; prep TLC=preparativethin layer chromatography; LCMS, LC/MS=liquid chromatography-massspectrometry

The following examples are provided to more fully illustrate the presentinvention, and shall not be construed as limiting the scope in anymanner. Unless stated otherwise, the following conditions were employed.All operations were carried out at room or ambient temperature (RT),that is, at a temperature in the range 18-25° C. Reactions are generallydone using commercially available anhydrous solvents under an inertatmosphere, either nitrogen or argon. Microwave reactions were doneusing a BIOTAGE Initiator™ or CEM Explorer® system. Evaporation ofsolvent was carried out using a rotary evaporator under reduced pressure(4.5-30 mmHg) with a bath temperature of up to 50° C. The course ofreactions was followed by thin layer chromatography (TLC) and/or tandemhigh performance liquid chromatography (HPLC) followed by electron spraymass spectroscopy (MS), herein termed LCMS, and any reaction times aregiven for illustration only. The structure of all final compounds wasassured by at least one of the following techniques: MS or protonnuclear magnetic resonance (1H NMR) spectrometry, and the purity wasassured by at least one of the following techniques: TLC or HPLC. ¹H NMRspectra were recorded on either a Varian Unity or a Varian Inovainstrument at 400, 500 or 600 MHz using the indicated solvent; whenline-listed, NMR data is in the form of delta values for majordiagnostic protons, given in parts per million (ppm) relative toresidual solvent peaks (multiplicity and number of hydrogens);conventional abbreviations used for signal shape are: s. singlet; d.doublet (apparent); t. triplet (apparent); m. multiplet; br. broad; etc.MS data were recorded on a Waters Micromass unit, interfaced with aHewlett-Packard (Agilent 1100) HPLC instrument, and operating onMassLynx/OpenLynx software; electrospray ionization was used withpositive (ES+) or negative ion (ES−) detection; and diode arraydetection. Purification of compounds by preparative reverse phase HPLCwas performed on a Gilson system using a YMC-Pack Pro C18 column (150×20mm i.d.) eluting at 20 mL/min with a water/acetonitrile (0.1% TFA)gradient (typically 5% acetonitrile to 95% acetonitrile) using a SunfirePrep C18 OBD 5 μM column (100×30 mm i.d.) eluting at 50 mL/min with awater/acetonitrile (0.1% TFA) gradient. Purification of compounds bypreparative thin layer chromatography (PTLC) was conducted on 20×20 cmglass plates coated with silica gel, commercially available fromAnaltech; or E. Merck. Flash column chromatography was carried out on aglass silica gel column using Kieselgel 60, 0.063-0.200 mm (SiO₂), or ona Biotage SiO₂ cartridge system using the Biotage Horizon and BiotageSP-1 systems; or a Teledyne Isco SiO₂ cartridge using the CombiFlashRfsystem. Chemical symbols have their usual meanings, and the followingabbreviations have also been used: h (hours), min (minutes), v (volume),w (weight), b.p. (boiling point), m.p. (melting point), L (litre(s)), mL(millilitres), g (gram(s)), mg (milligrams(s)), mol (moles), mmol(millimoles), eq or equiv (equivalent(s)), uM (micromolar), nM(nanomolar), ca (circa/about).

The following are representative procedures for the preparation ofintermediates used to prepare the final products described in theExamples that follow thereafter. These examples are provided for thepurpose of further illustration only and are not intended to belimitations on the disclosed invention.

It is understood that a chiral center in a compound may exist in the “S”or “R” stereo-configurations, or as a mixture of both. In some of theexamples for intermediate compounds and final compounds, such compoundshaving a racemic chiral center were separated into individualstereoisomers, for example, referred to as isomer A (or enantiomer A orthe like), which refers to the observed faster eluting isomer, andisomer B (or enantiomer B or the like), which refers to the observedslower eluting isomer, and each such isomer may be noted in the exampleas either the fast or slow eluting isomer. When a single “A” or “B”isomer intermediate is used to prepare a downstream compound, thedownstream compound may take the “A” or “B” designation that correspondsto the previously used intermediate.

Any Intermediates described below may be referred to herein by theirnumber preceded by “I-.” For illustration, in the example titled“Intermediate 2,” the racemic parent title compound would be referred toas Intermediate 2 (or I-2), and the separated stereoisomers are noted asIntermediates 2A and 2B (or I-2A and I-2B). In some examples, compoundshaving a chiral center were derived synthetically from a single isomerintermediate; e.g., Example 1 was made using stereoisomer I-1A.

Absolute stereochemistry of separate stereoisomers in the Examples andIntermediates was not determined unless stated otherwise in an Exampleor

Intermediate synthesis

Intermediate 1, 1A and 1B Ethyl3,3-dicyano-2-(4-fluorophenyl)-2-methylpropanoate and the S and RIsomers Thereof

Step A—Ethyl 2-(4-fluorophenyl)-2-oxoacetate: Into a flask was placed asolution of diethyl oxalate (28.5 g, 195 mmol) in THF (300 mL) which wascooled at −78° C. 4-Fluorophenylmagnesium bromide (150 mL, 1.0 M in THF)was added dropwise, and the resulting solution was stirred for 1.5 hwith warming to RT. The reaction was quenched by the addition ofsaturated aqueous NH₄Cl. The resulting solution was extracted with EtOAc(3×) and the organic layers were combined, dried over anhyd. Na₂SO₄, andfiltered. The filtrate was concentrated in vacuo to dryness. The residuewas purified by silica gel chromatography with EtOAc: PE (1%) to affordthe title compound.

Step B—Ethyl 3,3-dicyano-2-(4-fluorophenyl)acrylate: Into a flask wasplaced the intermediate from Step A (28.0 g, 143 mmol), malononitrile(37.7 g, 571 mmol), piperidine (2.5 mL), and EtOH (125 mL). Theresulting solution was stirred 16 h at reflux. Upon completion, theresulting mixture was concentrated in vacuo. The residue was purified bysilica gel chromatography with EtOAc:PE (10%) to afford the titlecompound.

Step C—Ethyl 3,3-dicyano-2-(4-fluorophenyl)-2-methylpropanoate: Into aflask was placed the intermediate from Step B (3.0 g, 12 mmol), THF (50mL), and lithium chloride (1.0 g, 23.6 mmol) which was cooled at 0° C.Subsequently, MeMgBr (7 mL) was added dropwise, and the resultingsolution was stirred for 1 h at 0° C. The reaction was then quenched bythe addition of water. The resulting solution was extracted with EtOAc(2×). The organic layers were combined, dried over anhyd. Na₂SO₄, andfiltered. The filtrate was concentrated in vacuo to dryness. The residuewas purified by silica gel chromatography with EtOAc: PE (25%) to affordthe title compound. The racemic material was resolved using chiral SFC(OJ column) to afford isomers I-1A (faster eluting) and I-1B (slowereluting) of the title compound. ¹H NMR (300 MHz, CDCl₃): δ 7.40-7.33(2H, m), 7.17-7.09 (2H, m), 4.45 (1H, s), 4.30 (2H, q, J=7.2 Hz), 1.99(3H, s), 1.26 (3H, t, J=7.2 Hz).

Intermediate 2, 2A and 2B Ethyl2-(4-chlorophenyl)-3,3-dicyano-2-methylpropanoate and the R and SIsomers Thereof

The title compound was prepared using essentially the same procedure asdescribed in Intermediate 1 with either commercial starting reagents orthose known in the literature. The racemic material was resolved using achiral SFC (OJ column) to afford isomer I-2A (faster eluting) and isomerI-2B (slower eluting) of the title compound. m/z=275 (M-1).

Intermediate 3, 3A and 3B Ethyl3,3-dicyano-2-(5-fluoropyridin-2-yl)-2-methylpropanoate and the R and SIsomers Thereof

Step A—Diethyl 2-(5-fluoropyridin-2-yl)malonate: Into a flask, wasplaced 2-bromo-5-fluoropyridine (20.0 g, 114 mmol), 1,3-diethylpropanedioate (54.5 g, 340 mmol), picolinic acid (5.6 g, 45 mmol),Cs₂CO₃ (143 g, 438 mmol), CuI (4.3 g, 23 mmol), and dioxane (500 mL).The resulting solution was stirred for 12 hat 100° C. The resultingsolution was quenched by the addition of water (300 mL). The resultingsolution was extracted with EtOAc (2×), the organic layers combined anddried over anhyd. Na₂SO₄, and concentrated in vacuo to dryness. Theresidue was purified by silica chromatography using EtOAc: PE (0-20%) toafford the title compound.

Step B—Ethyl 2-(5-fluoropyridin-2-yl)acetate: Into a 3-neckedround-bottom flask, was placed the intermediate from Step A (46 g,crude), NaCl (20 g, 342 mmol), water (6 mL), and DMSO (90 mL). Theresulting solution was stirred for 3 hat 180° C. Upon completion, theresulting solution was diluted with EtOAc, washed with water (5×) andthe organic layer was dried over anhyd. Na₂SO₄ and concentrated in vacuoto dryness. The residue was purified by silica chromatography usingEtOAc:PE (0-20%) to afford the title compound.

Step C—Ethyl 2-(5-fluoropyridin-2-yl)propanoate: Into a flask was placedTHF (200 mL) and LiHMDS (45 mL, 1.0 M). This was followed by dropwiseaddition of the intermediate from Step B (7.5 g, 41 mmol) with stirringat 0° C. After stirring the resulting solution for 1 h, a solution ofiodomethane (5.8 g, 41 mmol) in THF (10 mL) was added dropwise. Theresulting solution was stirred for 3 h at 0° C. The reaction was thenquenched by the addition of water. The resulting mixture was extractedwith EtOAc (3×), the organic layers combined and dried over anhyd.Na₂SO₄, and concentrated in vacuo to dryness. The residue was purifiedby silica chromatography using EtOAc:PE (0-20%) to afford the titlecompound.

Step D—Ethyl 2-bromo-2-(5-fluoropyridin-2-yl)propanoate: Into a flaskwas added the intermediate from Step C (1 g, 5 mmol) and THF (50 mL).This was followed by the addition of LiHMDS (5 mL, 1.0 M) dropwise withstirring at −78° C. The resulting solution was stirred for 30 min at−78° C. before NBS (1.2 g, 7.1 mmol) in THF (10 mL) was added, and thesolution was warmed to RT and stirred for 1 h. The reaction was thenquenched by the addition of water. The resulting solution was extractedwith EtOAc (3×) and the organic layers combined and dried over anhyd.Na₂SO₄. The solid was filtered and the eluent was concentrated in vacuoto dryness. The residue was purified by silica chromatography usingEtOAc: PE (0-10%) to afford the title compound.

Step E—Ethyl 3,3-dicyano-2-(5-fluoropyridin-2-y0-2-methylpropanoate:Into a flask was placed DMF (20 mL) and NaH (260 mg, 6.50 mmol, 60%).This was followed by the addition of malononitrile (460 mg, 6.96 mmol)with stirring at 0° C. The resulting solution was stirred for 30 min at0° C. To this was added the intermediate from Step D (950 mg, 3.44 mmol)in DMF dropwise with stirring at 0° C. The resulting solution wasstirred for 1 h at RT. Upon completion, the resulting solution wasquenched with water, and extracted with EtOAc. The organic layer wasdried over anhyd. Na₂SO₄ and concentrated in vacuo to dryness. Theresidue was purified by silica chromatography using EtOAc:PE (0-20%).The racemic material was resolved using a chiral SFC (IA column) toafford isomers I-3A (faster eluting) and I-3B (slower eluting) of thetitle compound. ¹H NMR: (300 MHz, CDCl₃): δ 8.44-8.45 (1H, dd, J=0.9,2.4 Hz), 7.47-7.57 (2H, m), 5.17 (1H, s), 4.19-4.29 (2H, m), 2.00 (3H,s), 1.22-1.27 (3H, t, J=6.9 Hz).

Intermediate 4, 4A and 4B Methyl 3,3-dicyano-2-methyl-2-phenylpropanoateand the R and S Isomers Thereof

The title compound was prepared using essentially the same procedure asdescribed in Intermediate 3 with either commercial starting reagents orthose known in the literature. The racemic material was resolved using achiral SFC (AD column) to afford isomer I-4A (faster eluting) and isomerI-4B (slower eluting) of the title compound. ¹H NMR (500 MHz, CDCl₃): δ7.44-7.42 (3H, m), 7.38-7.36 (2H, m), 4.50 (1H, s), 3.80 (3H, s), 2.00(3H, s).

Intermediate 5, 5A and 5B Ethyl3,3-dicyano-2-cyclopropyl-2-(4-fluorophenyl)propanoate and the R and SIsomers Thereof

Step A—Ethyl 2-cyclopropyl-2-oxoacetate: Into a flask was placed asolution of diethyl oxalate (28.5 g, 195 mmol) in THF (200 mL) which wascooled at −78° C. Cyclopropylmagnesium bromide (150 mL, 150 mmol, THF)was added dropwise, and the resulting solution was stirred for 2 h withwarming to RT. The reaction was quenched by the addition of saturatedaqueous NH₄Cl. The resulting solution was extracted with EtOAc (3×) andthe organic layers were combined, washed with brine, dried over anhyd.Na₂SO₄, and filtered. The filtrate was concentrated in vacuo to dryness.The residue was purified by silica gel chromatography with DCM: PE(40-60%) to afford the title compound.

Step B—Ethyl 3,3-dicyano-2-cyclopropylacrylate: Into a flask were placedthe intermediate from Step A (5.6 g, 39 mmol), malononitrile (2.6 g, 39mmol), EtOH (5 mL) and a solution of 3-aminopropanoic acid (175 mg) inwater (5 mL). The resulting solution was stirred 16 h at RT. Thereaction was quenched by the addition of water. The resulting solutionwas extracted with EtOAc (2×) and the organic layers were combined,washed with brine (2×), dried over anhyd. Na₂SO₄, and filtered. Thefiltrate was concentrated in vacuo to dryness. The residue was purifiedby silica gel chromatography with EtOAc: PE (5-15%) to afford the titlecompound.

Step C—Ethyl 3,3-dicyano-2-cyclopropyl-2-(4-fluorophenyl)propanoate:Into a flask was placed a solution of the intermediate from Step B (1.0g, 5.7 mmol) in THF (30 mL) which was cooled at −50° C.(4-Fluorophenyl)magnesium bromide (0.43 N in THF, 20 mL, 8.53 mmol) wasadded dropwise and the resulting solution was stirred for 1 h withwarming to RT. The reaction was quenched by the addition of saturatedNH₄Cl. The resulting solution was extracted with EtOAc (3×) and theorganic layers were combined, dried over anhyd. Na₂SO₄, and filtered.The filtrate was concentrated in vacuo to dryness. The residue waspurified by silica gel chromatography with EtOAc:PE (10%) to afford theracemic title compound. The racemic material was resolved using a chiralSFC (AS column) to afford isomer I-5A (faster eluting) and isomer I-5B(slower eluting) of the title compound. m/z=285.0 (M-1).

Intermediate 6 Methyl 3,3-dicyano-2,2-dimethylpropanoate

A 3 neck round bottom flask equipped with a mechanical stirrer,thermometer, condenser and nitrogen bubbler, was charged withmalononitrile (251 g, 3.80 moles) and THF (2 liters). t-BuOK (1M THF,3.80 L, 3.80 moles) was then added. The mixture was stirred at 50° C.for 0.5 h. Methyl 2-bromoisobutyrate (688 g, 3.80 moles) was added andthe reaction mixture was stirred overnight at 50° C. The reaction waspartitioned between aqueous 1 N HCl and EtOAc. The organic phase waswashed with brine, dried over anhyd. magnesium sulfate, filtered, andconcentrated to afford the title compound. ¹H NMR (400 MHz, CD₃CN): δ4.35 (1H, s) 3.73 (3H, s), 1.43 (6H, s).

EXAMPLE 1A4-Amino-2-[8-(3-fluorophenoxy)imidazo[1,2-a]pyrazin-6-yl]-5-(4-fluorophenyl)-5-methyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one

Step A—6-Bromo-8-(3-fluorophenoxy)imidazo[1,2-a]pyrazine: In a vial wasplaced 6,8-dibromoimidazo[1,2-a]pyrazine (205 mg, 0.740 mmol), Cs₂CO₃(482 mg, 1.481 mmol), 3-fluorophenol (73.7 μl, 0.814 mmol), and DMF (3.7mL). After 20 min, the reaction mixture was diluted with EtOAc (50 mL),and the solid precipitate was filtered. The remaining eluent wasconcentrated in vacuo to dryness. The residue was dissolved in EtOAc,washed with water and brine. The organic layer was dried over anhyd.

Na₂SO₄ and filtered. The filtrate was concentrated in vacuo to dryness.The residue was purified by silica gel chromatography with EtOAc:hexanes(10-80%) to afford the title compound. m/z=309.8 (M+H).

Step B—8-(3-Fluorophenoxy)imidazo[1,2-a]pyrazine-6-carbonitrile: Into avial was placed the intermediate from Step A (120 mg, 0.389 mmol), zinccyanide (45.7 mg, 0.389 mmol), and Pd(dppf)Cl₂ (28.5 mg, 0.039 mmol),which was secured with a pierce-able cap. The sealed vial was evacuatedand refilled with N₂ (3×). DMA (1.56 mL) was added and the reaction waswarmed at 120° C. After 18 h, the reaction was diluted with EtOAc andquenched with satd. aq. NaHCO₃, and the resulting mixture was filteredthrough a plug of CELITE. The solution was extracted with EtOAc (2×) andthe organic layers were combined, dried over anhyd. Na₂SO₄, filtered,and the filtrate was concentrated in vacuo to dryness. The residue waspurified by silica gel chromatography with EtOAc:hexanes (0-100%) toafford the title compound. m/z=254.9 (M+H).

Step C—8-(3-Fluorophenoxy)imidazo[1,2-a]pyrazine-6-carboximidamide: Intoa vial, purged with an inert atmosphere of nitrogen, was placed theintermediate from Step B (145 mg, 0.57 mmol). To this was addedamino(methyl)aluminum chloride (5.0 mL, 5.0 mmol, 1.0 M in toluene), andthe resulting mixture was warmed at 110° C. After 2 h, the reactionmixture was cooled to 0° C. The reaction was then quenched by theaddition of MeOH:DCM (1:4, 400 mL). After vigorous stirring, the solidwas filtered through a pad of CELITE. The resulting eluent wasconcentrated in vacuo to dryness. This afforded the HCl salt of8-(3-fluorophenoxy)imidazo[1,2-a]pyrazine-6-carboximidamide, which wasused without purification. m/z=272.1 (M+H).

StepD—4-Amino-2-[8-(3-fluorophenoxy)imidazo[1,2-a]pyrazin-6-yl]-5-(4-fluorophenyl)-5-methyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one:Into a vial, purged with an inert atmosphere of nitrogen, was placedt-BuOH (1.29 mL), the intermediate from Step C (70 mg, 0.26 mmol), I-1A(81 mg, 0.31 mmol) and KHCO₃ (78 mg, 0.77 mmol). The heterogeneousmixture was stirred at 80° C. for 16 h. The reaction mixture was cooledto RT and diluted with MeOH. The resulting precipitate was filtered andthe filtrate was concentrated in vacuo to dryness. The residue waspurified by silica gel chromatography with EtOAc:hexanes (10-100%) toafford the title compound. ¹H NMR (500 MHz, CD₃OD): δ 9.20 (1H, s), 8.13(1H, d, J=1.3 Hz), 7.78 (1H, d, J=1.3 Hz), 7.42 (1H, q, J=7.6 Hz),7.31-7.25 (4H, m), 7.06-6.95 (3H, m), 1.81 (3H, s); m/z=486.0 (M+H).

TABLE 1 Examples 2A-34A Using essentially the same procedures describedin Example 1A, the following compounds in Table 1 were prepared. ChiralEx starting No. Structure IUPAC Name material [M + H]⁺  2A

4-amino-5-(4- fluorophenyl)-5-methyl- 2-[8-(2,2,3,3,3-pentafluoropropoxy) imidazo[1,2-a]pyrazin- 6-yl]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin- 6-one I-1A 524.0  3B

4-amino-5-methyl- 2-[8-(2,2,3,3,3- pentafluoropropoxy)imidazo[1,2-a]pyrazin- 6-yl]-5-phenyl-5,7- dihydro-6H-pyrrolo[2,3-d]pyrimidin-6- one I-4B 506.0  4A

4-amino-2-[8-(2- fluorophenoxy) imidazo[1,2-a]pyrazin-6-yl]-5-(4-fluorophenyl)- 5-methyl-5,7-dihydro- 6H-pyrrolo[2,3-d]pyrimidin-6-one I-1A 486.0  5B

4-amino-2-[8-(2- fluorophenoxy) imidazo[1,2-a]pyrazin- 6-yl]-5-methyl-5-phenyl-5,7-dihydro- 6H-pyrrolo[2,3-d] pyrimidin-6-one I-4B 468.0  6A

4-amino-5-(4- fluorophenyl)-5- methyl-2-[8-(2,3,6- trifluorophenoxy)imidazo[1,2-a]pyrazin- 6-yl]-5,7-dihydro-6H- pyrrolo[2,3-d]pyrimidin-6-one I-1A 522.0  7B

4-amino-5-methyl- 5-phenyl-2-[8-(2,3,6- trifluorophenoxy)imidazo[1,2-a]pyrazin- 6-yl]-5,7-dihydro-6H- pyrrolo[2,3-d]pyrimidin-6-one I-4B 504.0  8B

4-amino-2-[8-(3- fluorophenoxy) imidazo[1,2-a]pyrazin- 6-yl]-5-methyl-5-phenyl-5,7-dihydro- 6H-pyrrolo[2,3-d] pyrimidin-6-one I-4B 468.0  9A

4-amino-5-(4- fluorophenyl)-5- methyl-2-(8- phenoxyimidazo[1,2-a]pyrazin-6- yl)-5,7-dihydro- 6H-pyrrolo[2,3-d] pyrimidin-6-oneI-1A 468.0 10B

4-amino-5-methyl- 2-(8-phenoxy- imidazo[1,2-a] pyrazin-6-yl)-5-phenyl-5,7-dihydro- 6H-pyrrolo[2,3-d] pyrimidin-6-one I-4B 450.0 11B

4-amino-5-methyl- 5-phenyl-2-[8- (2,3,4-trifluoro- phenoxy)imidazo[1,2-a]pyrazin-6- yl]-5,7-dihydro- 6H-pyrrolo[2,3-d] pyrimidin-6-oneI-4B 504.1 12B

4-amino-5-methyl- 5-phenyl-2-[8- (2,3,5-trifluoro- phenoxy)imidazo[1,2-a]pyrazin-6- yl]-5,7-dihydro- 6H-pyrrolo[2,3-d] pyrimidin-6-oneI-4B 504.1 13B

4-amino-2-[8- (2,3-difluoro- phenoxy)imidazo [1,2-a]pyrazin-6-yl]-5-methyl-5- phenyl-5,7- dihydro-6H- pyrrolo[2,3-d] pyrimidin-6-oneI-4B 485.9 14B

4-amino-5- cyclopropyl-5- (4-fluorophenyl)- 2-[8-(2,2,3,3,3-pentafluoropropoxy) imidazo[1,2-a] pyrazin-6-yl]-5,7- dihydro-6H-pyrrolo[2,3-d]pyrimidin- 6-one I-5B 549.9 15A

4-amino-2-[8-(2,3- difluorophenoxy) imidazo[1,2-a] pyrazin-6-yl]-5-(4-fluorophenyl)-5- methyl-5,7-dihydro- 6H-pyrrolo[2,3-d] pyrimidin-6-oneI-1A 503.9 16A

4-amino-5-(4- fluorophenyl)-5- methyl-2-[8-(2,3,4- trifluorophenoxy)imidazo[1,2-a] pyrazin-6-yl]-5,7- dihydro-6H-pyrrolo [2,3-d]pyrimidin-6-one I-1A 521.9 17A

4-amino-5-(4- fluorophenyl)-5- methyl-2-[8-(2,3,5- trifluorophenoxy)imidazo[1,2-a] pyrazin-6-yl]-5,7- dihydro-6H-pyrrolo [2,3-d]pyrimidin-6-one I-1A 521.9 18A

4-amino-2-[8-(3,4- difluorophenoxy) imidazo[1,2-a] pyrazin-6-yl]-5-(4-fluorophenyl)- 5-methyl-5,7- dihydro-6H- pyrrolo[2,3-d]pyrimidin-6-one I-1A 503.9 19A

4-amino-2-[8-(2,4- difluorophenoxy) imidazo[1,2-a] pyrazin-6-yl]-5-(4-fluorophenyl)- 5-methyl-5,7- dihydro-6H- pyrrolo[2,3-d]pyrimidin-6-one I-1A 504.1 20A

4-amino-2-[8-(4- fluorophenoxy) imidazo[1,2-a] pyrazin-6-yl]-5-(4-fluorophenyl)- 5-methyl-5,7- dihydro-6H- pyrrolo[2,3-d]pyrimidin-6-one I-1A 486.1 21A

4-amino-5-(4- fluorophenyl)-5- methyl-2-(8-{[5- (trifluoromethyl)pyridin-3-yl]oxy} imidazo[1,2-a] pyrazin-6-yl)-5,7- dihydro-6H-pyrrolo[2,3-d] pyrimidin-6-one I-1A 537.1 22A

4-amino-2-[8- (cyclohexyloxy) imidazo[1,2-a] pyrazin-6-yl]-5-(4-fluorophenyl)- 5-methyl-5,7- dihydro-6H- pyrrolo[2,3-d]pyrimidin-6-one I-1A 474.1 23A

4-amino-2-[8-(3,5- difluorophenoxy) imidazo[1,2-a] pyrazin-6-yl]-5-(4-fluorophenyl)- 5-methyl-5,7- dihydro-6H- pyrrolo[2,3-d]pyrimidin-6-one I-1A 504.0 24

4-amino-2-[8-(3,5- difluorophenoxy) imidazo[1,2-a] pyrazin-6-yl]-5,5-dimethyl-5,7- dihydro-6H- pyrrolo[2,3-d] pyrimidin-6-one I-6 424.0 25A

4-amino-2-[8-(2,5- difluorophenoxy) imidazo[1,2-a] pyrazin-6-yl]-5-(4-fluorophenyl)- 5-methyl-5,7- dihydro-6H- pyrrolo[2,3-d]pyrimidin-6-one I-1A 504.0 26

4-amino-2-[8-(2,5- difluorophenoxy) imidazo[1,2-a] pyrazin-6-yl]-5,5-dimethyl-5,7- dihydro-6H- pyrrolo[2,3-d] pyrimidin-6-one I-6 424.0 27A

4-amino-5-(4- chlorophenyl)-2- [8-(2,5-difluoro- phenoxy)imidazo[1,2-a]pyrazin-6- yl]-5-methyl-5,7- dihydro-6H- pyrrolo[2,3-d]pyrimidin-6-one I-2A 520.0 28A

4-amino-5-(4- chlorophenyl)-2- {8-[(4,4- difluorocyclohexyl)oxy]imidazo[1,2-a] pyrazin-6-yl}-5- methyl-5,7-dihydro-6H-pyrrolo[2,3-d] pyrimidin-6-one I-2A 526.2 29A

4-amino-5-(4- fluorophenyl)-5- methyl-2-[8- (pyridin-3-yloxy)imidazo[1,2-a] pyrazin-6-yl]-5,7- dihydro-6H- pyrrolo[2,3-d]pyrimidin-6-one I-1A 469.2 30A

4-amino-5-(4- chlorophenyl)-5- methyl-2-[8- (pyridin-3-yloxy)imidazo[1,2-a] pyrazin-6-yl]-5,7- dihydro-6H- pyrrolo[2,3-d]pyrimidin-6-one I-2A 485.1 31A

4-amino-2-{8- [(3,3-difluoro- cyclobutyl) methoxy]imidazo[1,2-a]pyrazin-6- yl}-5-(4-fluoro- phenyl)-5-methyl- 5,7-dihydro-6H-pyrrolo[2,3-d] pyrimidin-6-one I-1A 496.1 32A

4-amino-5-(4- chlorophenyl)-2- {8-[(3,3-difluoro- cyclobutyl)methoxy]imidazo [1,2-a]pyrazin-6- yl}-5-methyl-5,7- dihydro-6H-pyrrolo[2,3-d] pyrimidin-6-one I-2A 512.2 33B

4-amino-2-{8- [(3,3-difluoro- cyclobutyl) methoxy]imidazo[1,2-a]pyrazin-6- yl}-5-(5-fluoro- pyridin-2-yl)- 5-methyl-5,7-dihydro-6H- pyrrolo[2,3-d] pyrimidin-6-one I-3B 497.2 34A

4-amino-5-(4- fluorophenyl)- 5-methyl-2- {8-[(2,2,3,3,3-pentafluoropropyl) amino]imidazo [1,2-a]pyrazin-6- yl}-5,7-dihydro-6H-pyrrolo[2,3-d] pyrimidin-6-one I-1A 523.2

EXAMPLE 35A4-Amino-2-(8-(3-fluorophenoxy)-2-(trifluoromethyl)imidazo[1,2-a]pyrazin-6-yl)-5-(4-fluorophenyl)-5-methyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one

Step A—6,8-dibromo-2-(trifluoromethyl)imidazo[1,2-a]pyrazine: Into aflask, was placed 3,5-dibromopyrazin-2-amine (20.0 g, 79.1 mmol), DMA(100 mL), and 3-bromo-1,1,1-trifluoropropan-2-one (37.7 g, 197 mmol).The resulting solution was stirred 16 h at 90° C. The reaction wasquenched by the addition of saturated sodium bicarbonate, and theresulting solution was extracted with EtOAc (3×). The combined organiclayers were washed with brine (2×), dried over anhyd. Na₂SO₄, filtered,and concentrated in vacuo to dryness. The residue was purified by silicachromatography using EtOAc:PE (20%) to afford the title compound.

StepsB-E—4-Amino-2-(8-(3-fluorophenoxy)-2-(trifluoromethyl)imidazo[1,2-a]pyrazin-6-yl)-5-(4-fluorophenyl)-5-methyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one:The title compound was prepared utilizing the intermediate from Step Aaccording to the procedure described in Steps A-E of Example 1A. ¹H NMR(300 MHz, CDCl₃): δ 9.06 (1H, s), 8.64 (1H, brs), 8.13 (1H, s),7.41-7.25 (4H, m), 7.09-7.03 (2H, m), 6.97-6.92 (2H, m), 4.90 (2H, brs),1.81 (3H, s); m/z=554 (M+H).

TABLE 2 Examples 36A-38A Using essentially the same procedures describedin example 35A, the following compounds in Table 2 were prepared. ChiralEx. starting No. Structure IUPAC Name material [M + H]⁺ 36A

4-amino-5-(4- fluorophenyl)- 5-methyl-2-(8- phenoxy-2- (trifluoromethyl)imidazo[1,2-a] pyrazin-6-yl)- 5H-pyrrolo[2,3-d] pyrimidin-6(7H)- oneI-1A 536.1 37A

4-amino-2-(8- (2,3-difluoro- phenoxy)-2- (trifluoromethyl)imidazo[1,2-a] pyrazin-6-yl)-5- (4-fluorophenyl)- 5-methyl-5H-pyrrolo[2,3-d] pyrimidin-6(7H)- one I-1A 572.0 38A

4-amino-2-[2- cyclopropyl-8-(3- fluorophenoxy) imidazo[1,2-a]pyrazin-6-yl]-5- (4-fluorophenyl)- 5-methyl-5,7- dihydro-6H-pyrrolo[2,3-d] pyrimidin-6-one I-1A 526.1

EXAMPLE 39A4-Amino-5-(4-fluorophenyl)-5-methyl-2-(8-propoxyimidazo[1,2-a]pyrazin-6-yl)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one

Step A—8-(Methylthio)imidazo[1,2-a]pyrazine-6-carboximidamide: Into aflask, purged with an inert atmosphere of nitrogen, was placed8-(methylthio)imidazo[1,2-a]pyrazine-6-carbonitrile (3.5 g, 18 mmol) andtoluene (50 mL). To this was added amino(methyl)aluminum chloride (196mL, 58.9 mmol, 0.3 M in toluene) and the resulting mixture was warmed at80° C. After 16 h, the reaction mixture was cooled to 0° C. The reactionwas quenched by the addition of MeOH:DCM (1:4, 200 mL). The solid wasfiltered through a pad of celite, and the resulting eluent wasconcentrated in vacuo to dryness to afford the title compound as the HClsalt.

StepB—4-Amino-5-(4-fluorophenyl)-5-methyl-2-(8-(methylthio)imidazo[1,2-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one:Into a vial, purged with an inert atmosphere of nitrogen, was placedt-BuOH (8.8 mL), the intermediate from Step A (425 mg, 2.05 mmol), I-1A(656 mg, 2.67 mmol) and KHCO₃ (616 mg, 6.15 mmol). The heterogeneousmixture was stirred at 70° C. for 16 h. The reaction mixture was cooledto RT and quenched with H₂O (25 mL). The resulting solution wasextracted with EtOAc (3×) and the organic layers were combined, anddried over anhyd. Na₂SO₄. The solid was filtered and the filtrate wasconcentrated in vacuo to dryness. The residue was purified by silica gelchromatography with EtOAc:hexanes (20-100%) to afford the titlecompound.

StepC—4-Amino-5-(4-fluorophenyl)-5-methyl-2-(8-(methylsulfonyl)imidazo[1,2-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one:To a mixture of finely ground Oxone® (1.82 g, 2.97 mmol) in ACN (5.5 mL)was added conc. sulfuric acid (1.27 mL, 23.7 mmol) at 0° C. After 5 min,the intermediate from Step B (500 mg, 1.19 mmol) was added in a singleportion. The reaction was slowly warmed to RT. After 1.5 h, saturatedaqueous NaHCO₃ (30 mL) was added and the mixture was extracted withEtOAc (3×). The organic layers were combined and dried over Na₂SO₄. Thesolid was filtered and the filtrate was concentrated in vacuo to drynessto afford the title compound, which was not further purified. m/z=454.1(M+H).

StepD—4-Amino-5-(4-fluorophenyl)-5-methyl-2-(8-propoxyimidazo[1,2-a]pyrazin-6-yl)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one:NaH (30.4 mg, 0.761 mmol) was added to a solution of the intermediatefrom Step C (115 mg, 0.254 mmol) in 1-propanol (1.3 mL) at RT. After 5min, the volatiles were removed and the residue was dissolved in EtOAc(150 mL) and washed with water (1×). The aqueous layer was extractedwith EtOAc (3×). The combined organic layers were washed with saturatedaqueous NH₄Cl (1×) and brine (1×), dried over anhyd. Na₂SO₄, filtered,and concentrated in vacuo to dryness. The residue was purified by silicachromatography using EtOAc:hexanes (0-100%) to afford the titlecompound. ¹H NMR (500 MHz, CD₃OD): δ 9.05 (1H, s), 7.99 (1H, s), 7.64(1H, s), 7.32 (2H, dd, J=8.6, 5.2 Hz), 7.05 (2H, t, J=8.6 Hz), 4.64 (2H,t,

J=6.7 Hz), 1.91-1.86 (2H, m), 1.83 (3H, s), 1.09 (3H, t, J=7.4 Hz);m/z=434.1 (M+H).

EXAMPLE 40A4-Amino-5-(4-chlorophenyl)-2-{8-[(2-methoxyethyl)amino]imidazo[1,2-a]pyrazin-6-yl}-5-methyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one

StepA-C—4-Amino-5-(4-chlorophenyl)-5-methyl-2-(8-(methylsulfonyl)imidazo[1,2-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one:The sulfone was prepared in its enantiopure form using essentially thesame procedure as described in Example 39A with Ex-39A intermediate Aand I-2A following the procedures described in steps B-C. m/z=470.0(M+H).

StepD—4-Amino-5-(4-chlorophenyl)-2-{8-[(2-methoxyethyl)amino]imidazo[1,2-a]pyrazin-6-yl}-5-methyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one:Sodium hydride (18 mg, 0.45 mmol) was added to a mixture of theintermediate from Steps A-C (70 mg, 0.15 mmol) and 2-methoxyethylamine(1 mL, 0.15 mmol), at RT. After 5 min, the reaction was diluted withEtOAc (100 mL) and washed with water (1×). The aqueous layer wasextracted with EtOAc (3×). The combined organic layers were washed withsaturated aqueous NH₄Cl (1×) and brine (1×), dried over anhyd. Na₂SO₄,filtered, and concentrated in vacuo to dryness. The crude residue waspurified by RP-HPLC with 10-60% ACN:water (0.05% TFA), followed bybasifying with saturated aqueous NaHCO₃ and extraction with EtOAc toafford the title compound. ¹H NMR (500 MHz, DMSO-d₆): δ 8.54 (1H, s),8.04 (1H, s), 7.55 (1H, s), 7.39 (2H, d, J=8.4 Hz), 7.26 (2H, d, J=8.4Hz), 7.23 (1H, t, J=5.7 Hz), 6.30 (2H, br s), 3.75 (2H, dd, J=6.2, 6.1Hz), 3.58 (2H, t, J=6.0 Hz), 3.29 (3H, s), 1.75 (3H, s); m/z=465.0(M+H).

TABLE 3 Examples 41A-64A Using essentially the same procedures describedin examples 39A & 40A, the following compounds in Table 3 were prepared.Chiral Ex. starting No. Structure IUPAC Name material [M + H]⁺ 41A

4-amino-2-{8-[2- (2,2-difluoro- cyclopropyl)ethoxy] imidazo[1,2-a]pyrazin-6-yl}-5- (4-fluorophenyl)- 5-methyl-5,7- dihydro-6H-pyrrolo[2,3-d] pyrimidin-6-one I-1A 496.1 42A

4-amino-2-{8-[2- (3,3-difluoro- cyclobutyl)ethoxy] imidazo[1,2-a]pyrazin-6-yl}-5- (4-fluorophenyl)- 5-methyl-5,7- dihydro-6H-pyrrolo[2,3-d] pyrimidin-6-one I-1A 510.1 43A

4-amino-2-[8- (cyclohexyl- methoxy)imidazo [1,2-a]pyrazin- 6-yl]-5-(4-fluorophenyl)-5- methyl-5,7- dihydro-6H- pyrrolo[2,3-d] pyrimidin-6-oneI-1A 488.2 44A

4-amino-2-[8- (2-cyclopropyl- ethoxy)imidazo [1,2-a]pyrazin- 6-yl]-5-(4-fluorophenyl)- 5-methyl-5,7- dihydro-6H- pyrrolo[2,3-d] pyrimidin-6-oneI-1A 460.1 45A

4-amino-2-[8- (cyclopentyl- methoxy)imidazo [1,2-a]pyrazin-6-yl]-5-(4-fluoro- phenyl)-5- methyl-5,7- dihydro-6H- pyrrolo[2,3-d]pyrimidin-6-one I-1A 474.2 46A

4-amino-2-[8- (cyclopentyl- oxy)imidazo [1,2-a]pyrazin- 6-yl]-5-(4-fluorophenyl)- 5-methyl-5,7- dihydro-6H- pyrrolo[2,3-d] pyrimidin-6-oneI-1A 460.1 47A

4-amino-5-(4- chlorophenyl)- 5-methyl-2-[8- (2,2,3,3,3- pentafluoro-propoxy)imidazo [1,2-a]pyrazin- 6-yl]-5,7- dihydro-6H- pyrrolo[2,3-d]pyrimidin-6-one I-2A 540.0 48A

4-amino-2-[8- (benzyloxy) imidazo[1,2-a] pyrazin-6-yl]-5-(4-chlorophenyl)- 5-methyl-5,7- dihydro-6H- pyrrolo[2,3-d]pyrimidin-6-one I-2A 498.0 49A

4-amino-5-(4- chlorophenyl)- 5-methyl-2-(8- propoxyimidazo[1,2-a]pyrazin- 6-yl)-5,7- dihydro-6H- pyrrolo[2,3-d] pyrimidin-6-oneI-2A 450.1 50A

4-amino-5-(4- chlorophenyl)- 2-[8-(2-cyclo- propylethoxy) imidazo[1,2-a]pyrazin-6-yl]- 5-methyl-5,7- dihydro-6H- pyrrolo[2,3-d] pyrimidin-6-oneI-2A 476.1 51A

4-amino-5-(4- fluorophenyl)- 5-methyl-2-[8- (2-methyl- propoxy)imidazo[1,2-a]pyrazin- 6-yl]-5,7- dihydro-6H- pyrrolo[2,3-d] pyrimidin-6-oneI-1A 448.1 52A

4-amino-5-(4- fluorophenyl)- 2-{8-[(2- methoxyethyl) amino]imidazo[1,2-a]pyrazin- 6-yl}-5- methyl-5,7- dihydro-6H- pyrrolo[2,3-d]pyrimidin-6-one I-1A 449.1 53A

4-amino-2-(8- {[(3,3-difluoro- cyclobutyl) methyl]amino} imidazo[1,2-a]pyrazin-6-yl)- 5-(4-fluoro- phenyl)-5- methyl-5,7- dihydro-6H-pyrrolo[2,3-d] pyrimidin-6-one I-1A 495.1 54A

4-amino-2-(8- {[(1-ethyl- cyclopropyl) methyl]amino} imidazo[1,2-a]pyrazin-6-yl)- 5-(4-fluoro- phenyl)-5- methyl-5,7- dihydro-6H-pyrrolo[2,3-d] pyrimidin-6-one I-1A 473.0 55A

4-amino-2-{8- [(cyclohexyl- methyl)amino] imidazo[1,2-a] pyrazin-6-yl}-5-(4-fluoro- phenyl)-5- methyl-5,7- dihydro-6H- pyrrolo[2,3-d]pyrimidin-6-one I-1A 487.1 56A

4-amino-5-(4- chlorophenyl)-2- (8-{[(2,2- dimethylcyclo- propyl)methyl]amino}imidazo [1,2-a]pyrazin- 6-yl)-5-methyl- 5,7-dihydro- 6H-pyrrolo[2,3-d]pyrimidin- 6-one I-2A 489.1 57A

4-amino-5-(4- chlorophenyl)- 2-(8-{[(1- ethylcyclo- propyl)methyl]amino}imidazo [1,2-a]pyrazin- 6-yl)-5- methyl-5,7- dihydro-6H-pyrrolo[2,3-d] pyrimidin-6-one I-2A 489.1 58A

4-amino-5-(4- chlorophenyl)- 2-(8-{[(3,3- difluorocyclo- butyl)methyl]amino}imidazo [1,2-a]pyrazin- 6-yl)-5-methyl- 5,7-dihydro-6H-pyrrolo[2,3-d] pyrimidin-6-one I-2A 511.1 59A

4-amino-5-(4- chlorophenyl)- 5-methyl-2-{8- [(tetrahydro-2H-pyran-4-ylmethyl) amino]imidazo [1,2-a]pyrazin-6- yl}-5,7-dihydro-6H-pyrrolo[2,3-d] pyrimidin-6-one I-2A 505.1 60A

4-amino-2-[8- (benzylamino) imidazo[1,2-a] pyrazin-6-yl]- 5-(4-chloro-phenyl)-5- methyl-5,7- dihydro-6H- pyrrolo[2,3-d] pyrimidin-6-one I-2A497.1 61A

4-amino-5-(4- chlorophenyl)- 5-methyl-2- {8-[(2,2,3,3,3- pentafluoro-propyl)amino] imidazo[1,2-a] pyrazin-6-yl}- 5,7-dihydro- 6H-pyrrolo[2,3-d]pyrimidin- 6-one I-2A 539.1 62A

4-amino-5-(4- fluorophenyl)- 5-methyl-2-[8- (propylsulfanyl)imidazo[1,2-a] pyrazin-6-yl]- 5,7-dihydro- 6H-pyrrolo [2,3-d]pyrimidin-6-one I-1A 450.0 63A

4-amino-5-(4- fluorophenyl)- 5-methyl-2-{8- [(2-methylpropyl)sulfanyl]imidazo [1,2-a]pyrazin-6- yl}-5,7-dihydro- 6H-pyrrolo[2,3-d]pyrimidin-6-one I-1A 464.2 64A

4-amino-5-(4- fluorophenyl)- 5-methyl-2-{8- [(3,3,3-trifluoro-propyl)sulfanyl] imidazo[1,2-a] pyrazin-6-yl}- 5,7-dihydro-6H-pyrrolo[2,3-d] pyrimidin-6-one I-1A 504.1

TABLE 4 Examples 65A-74 Using essentially the same procedures describedin examples 39A-40A, the following compounds in Table 4 were prepared.These compounds began with chiral intermediate and contain a secondstereocenter. For some examples the diasteoromers were separated or thechiral source was purchased. Chiral source or chiral Ex. resolution No.Structure IUPAC Name column [M + H]⁺ 65A

4-amino-5-(4- fluorophenyl)- 5-methyl-2-[8- (1-methyl- butoxy)imidazo[1,2-a]pyrazin- 6-yl]-5,7- dihydro-6H- pyrrolo[2,3-d] pyrimidin-6-one(rac)-2- pentanol 462.1 66A

4-amino-5-(4- chlorophenyl)- 5-methyl-2- [8-(tetrahydro- 2H-pyran-3-ylmethoxy) imidazo[1,2-a] pyrazin-6-yl]- 5,7-dihydro- 6H-pyrrolo [2,3-d]pyrimidin-6- one (fast eluting) CHIRALPAK IC 506.1 67B

4-amino-5-(4- chlorophenyl)- 5-methyl-2- [8-(tetrahydro- 2H-pyran-3-ylmethoxy) imidazo[1,2-a] pyrazin-6-yl]- 5,7-dihydro- 6H-pyrrolo [2,3-d]pyrimidin-6- one (slow eluting) CHIRALPAK IC 506.1 68A

4-amino-5-(4- chlorophenyl)- 5-methyl-2-[8- (tetrahydro- 2H-pyran-2-ylmethoxy) imidazo[1,2-a] pyrazin-6-yl]- 5,7-dihydro- 6H-pyrrolo [2,3-d]pyrimidin-6- one (fast eluting) CHIRALPAK AS 506.1 68B

4-amino-5-(4- chlorophenyl)- 5-methyl-2-[8- (tetrahydro- 2H-pyran-2-ylmethoxy) imidazo[1,2-a] pyrazin-6-yl]- 5,7-dihydro- 6H-pyrrolo [2,3-d]pyrimidin-6- one (slow eluting) CHIRALPAK AS 506.1 69A

4-amino-5-(4- chlorophenyl)- 5-methyl-2- {8-[(1S)-1- phenylethoxy]imidazo[1,2-a] pyrazin-6-yl}- 5,7-dihydro- 6H-pyrrolo [2,3-d]pyrimidin-6- one (fast eluting) (S)-1-phenyl- ethanol 512.1 70

4-amino-5-(4- fluorophenyl)- 5-methyl-2-{8- [(3,3,3- trifluoro-2-methylpropyl) amino]imidazo [1,2-a]pyrazin- 6-yl}-5,7- dihydro-6H-pyrrolo[2,3-d] pyrimidin-6- one (rac) 3,3,3- trifluoro-2- methylpropan-1-amine 501.2 71A

4-amino-5-(4- chlorophenyl)- 5-methyl-2-{8- [(tetrahydro- 2H-pyran-2-ylmethyl) amino]imidazo [1,2-a]pyrazin- 6-yl}-5,7- dihydro-6H-pyrrolo[2,3-d] pyrimidin-6- one (fast eluting) CHIRALPAK AS 505.1 71B

4-amino-5-(4- chlorophenyl)- 5-methyl-2- {8-[(tetrahydro- 2H-pyran-2-ylmethyl) amino]imidazo [1,2-a]pyrazin- 6-yl}-5,7- dihydro-6H-pyrrolo[2,3-d] pyrimidin-6- one (slow eluting) CHIRALPAK AS 505.1 72A

4-amino-5-(4- chlorophenyl)- 5-methyl-2-{8- [(tetrahydro- 2H-pyran-3-ylmethyl) amino]imidazo [1,2-a]pyrazin- 6-yl}-5,7- dihydro-6H-pyrrolo[2,3-d] pyrimidin-6- one (fast eluting) CHIRALPAK IC 505.1 72B

4-amino-5-(4- chlorophenyl)- 5-methyl-2-{8- [(tetrahydro- 2H-pyran-3-ylmethyl) amino]imidazo [1,2-a]pyrazin- 6-yl}-5,7- dihydro-6H-pyrrolo[2,3-d] pyrimidin-6- one (slow eluting) CHIRALPAK IC 505.1 73

4-amino-5-(4- chlorophenyl)- 5-methyl-2-{8- [(1-phenylethyl)amino]imidazo [1,2-a]pyrazin- 6-yl}-5,7- dihydro-6H- pyrrolo[2,3-d]pyrimidin-6- one (R)-(+)-1- phenyl- ethylamine 511.2 74

4-amino-5-(4- chlorophenyl)- 5-methyl-2- {8-[(1- phenylethyl)amino]imidazo [1,2-a]pyrazin- 6-yl}-5,7- dihydro-6H- pyrrolo[2,3-d]pyrimidin-6- one (S)-(−)-1- phenyl- ethylamine 511.2

Biological Assay 1: Cell-Based sGC Functional Assay (CASA Assay)Rationale

sGC is a heme-containing enzyme that converts GTP to secondary messengercGMP. Increases in cGMP levels affect several physiological processesincluding vasorelaxation through multiple downstream pathways. The rateby which sGC catalyzes cGMP formation is greatly increased by NO and byrecently discovered NO-independent activators and stimulators.Heme-dependent activators (HDAs) preferentially activate sGC containinga ferrous heme group. To determine the effect of sGC activators onenzyme activity, the CASA assay was developed to monitor the generationof cGMP in a cell line that stably expresses the heterodimeric sGCprotein.

Methods

A CHO-K1 cell line stably expressing the sGC α1/β1 heterodimer wasgenerated using a standard transfection protocol. CHO-K1 cells weretransfected with plasmids pIREShyghsGCα1 and pIRESneo-hsGCβ1simultaneously using FUGENE reagent. Clones that stably express bothsubunits were selected with hygromycin and neomycin for ˜2 weeks. Clone#7 was chosen for the assay and was designated CHO-K1/sGC. CHO-K1/sGCcells were maintained in F-K12 medium containing 10% heat-inactivatedFetal Bovine Serum (FBS), 100 μg/mL penicillin/streptomycin, 0.5 mg/mLhygromycin and 0.25 mg/mL G418. The cells were then cryopreserved inLN2. On the day of the assay, cells were thawed and resuspended in EBSSAssay Buffer (Sigma, E3024) supplemented with 5 mM MgCl₂, 10 mM HEPES(4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid) and 0.05% BSA(bovine serum albumin) (EAB) and cell density was then adjusted to4×105/mL with EAB. IBMX (3-isobutyl-1-methylxanthin, 0.5 mM) was addedto inhibit degradation of cGMP. Compounds were diluted from DMSO stocksolutions and added to the assay at a final DMSO concentration of 2.5%.Cells were incubated with compounds in the presence and absence of 1 μMof Diethylenetriamine/nitric oxide adduct (DETA-NO; Sigma, 17018) for 1hr at 37° C. At the end of the incubation period, the reaction wasterminated and the cells were lysed with the detection reagents fromCisbio Kits. The level of intracellular cGMP was determined using anHTRF-based assay kit (CisBio, 62GM2PEC), which detects the displacementof a fluorescence labeled cGMP from its specific antibody. The cGMPproduced by test compounds was directly compared to the maximum cGMPproduction (this value was set to equal 100% activation.) of thepublished sGC-HDA Compound A:

(Example 1 in WO 2010/065275, published Jun. 10, 2010). The testcompounds' activities were then expressed as a percentage of Compound A,the standard in every experiment. This percent activation was calculatedeither in the presence or absence of DETA-NO which was then plotted. IPand maximum fold induction was derived using ADA analysis software for4P fit.

The compounds in the Examples of the instant invention had inflectionpoints (IP) less than or equal to 10 μM and many had IPs less than orequal to about 1 μM. Most preferred compounds had an IP of less than orequal to about 500 nM. Data for the compounds of the Examples isprovided in Table 5.

TABLE 5 Ex. No. IP (nM) % Act.  1A 17 110  2A 317 127  3B 416 97  4A 62100  5B 80 107  6A 499 89  7B 1025 112  8B 22 110  9A 28 124 10B 45 12711B 138 104 12B 47 99 13B 14 109 14B 534 96 15A 23 104 16A 37 89 17A 17100 18A 10 98 19A 74 109 20A 42 109 21A 1065 137 22A 171 107 23A 16 10024 238 89 25A 32 97 26 718 105 27A 47 128 28A 1164 139 29A 422 158 30A171 168 31A 145 98 32A 157 129 33B 1035 112 34A 164 117 35A 468 94 36A1473 129 37A 719 83 38A 748 92 39A 148 109 40A 85 117 41A 644 94 42A1346 119 43A 17 116 44A 60 100 45A 13 110 46A 912 108 47A 157 91 48A 26106 49A 30 117 50A 12 106 51A 27 127 52A 244 101 53A 948 110 54A 266 9855A 35 92 56A 51 110 57A 47 123 58A 163 109 59A 701 167 60A 7 72 61A 165116 62A 142 99 63A 10 93 64A 73 67 65A 461 101 66A 1706 115 67B 501 9468A 324 86 68B 633 85 69A 833 103 70 291 89 71A 175 96 71B 143 95 72A1076 96 72B 412 94 73 336 81 74 231 87

Acute Efficacy in Spontaneously Hypertensive Rats (SHR)

Spontaneously hypertensive rats (SHR, male, Charles River) wereimplanted with DSI TA11 PA-C40 telemetry device (Data Sciences, Inc.,St. Paul, Minn.) under isoflurane or ketamine/metomidine anesthesia. Thetelemetry unit catheter was inserted into the descending aorta via thefemoral artery and the telemetry device was implanted subcutaneously inthe left flank area. Animals were allowed to recover from surgery for 14days before the start of any studies. Blood pressure, heart rate, andactivity signals from conscious, freely moving rats were recordedcontinuously for 30 seconds every 10 minutes. On the day prior toadministration of compound, a single oral dose of vehicle (10%transcutol/20% Cremophor/70% water) was administered to all animals toestablish baseline control data. The blood pressure lowering efficacy ofcompound (PO) or vehicle was evaluated following a single oral gavage.Data were collected as hourly averages, and changes in blood pressurewere calculated by subtracting control baseline data on an hourly basis.Animals were maintained on normal diet with a 12 hour light-dark cycle.

Maximum peak decreases of systolic blood pressure (SBP) in SHR at aparticular P.O. dose (mpk milligrams per kilogram) for the followingrepresentative compounds are provided below in Table 6.

-   Category A=SBP in SHRs <20 mmHg; Category B=SBP in SHRs 20-40 mmHg;-   Category C=SBP in SHRs >40 mmHg

TABLE 6 Dose, Ex. No. P.O. mpk Category  1A 0.3 B  2A 3.0 B  4A 1.0 C10B 0.3 B 30A 1.0 B 32A 1.0 B 34A 3.0 A 39A 1.0 C 40A 1.0 B 47A 1.0 B49A 0.3 B 50A 0.3 B 51A 0.3 B 61A 3.0 B 62A 1.0 B

1. A compound having structural Formula I:

or a pharmaceutically acceptable salt thereof wherein: C* indicates apotential chiral carbon atom; X is (1) O, (2) NH, or (3) S; R¹ is (1)phenyl unsubstituted or substituted by 1 to 3 halo, (2) (C₁₋₆)alkylunsubstituted or substituted by (C₁₋₃)alkyl, (3) halo(C₁₋₆)alkyl, (4)(C₃₋₇)cycloalkyl unsubstituted or substituted by 1 to 2 halo, (5) 5- or6-membered heteroaryl containing 1, 2, or 3 heteroatoms independentlyselected from N, O and S, wherein the heteroaryl is unsubstituted orsubstituted by 1 to 2 halo, (C₁₋₃)alkyl, or halo(C₁₋₃)alkyl, (6)—(C₁₋₃)alkyl-(C₃₋₇)cycloalkyl, wherein the cycloalkyl is unsubstitutedor substituted by 1 to 2 (C₁₋₃)alkyl, or halo, (7) —(C₁₋₃)alkyl-phenyl,wherein phenyl is unsubstituted or substituted by 1 to 3 halo, or (8)—(C₁₋₃)alkyl-heterocyclyl containing 1 or 2 heteroatoms independentlyselected from N and O, wherein the heterocyclyl is a 4-7 membered ring;R² is (1) (C₁₋₃)alkyl, or (2) (C₃₋₇)cycloalkyl; R³ is (1) phenylunsubstituted or substituted by 1 to 2 halo, (2) five- or six-memberedheteroaryl containing 1, 2, or 3 heteroatoms independently selected fromN, O and S, wherein heteroaryl is unsubstituted or substituted by 1 to 2halo, or (3) (C₁₋₆)alkyl; and R⁴ is (1) hydrogen, (2) (C₁₋₃)alkyl, (3)halo(C₁₋₃)alkyl, or (4) (C₃₋₆)cycloalkyl.
 2. The compound of claim 1, ora pharmaceutically acceptable salt thereof wherein: R¹ is (C₁₋₆)alkyl;halo(C₁₋₆)alkyl; (C₃₋₇)cycloalkyl unsubstituted or substituted by 1 to 2halo; —(C₁₋₃)alkyl-(C₃₋₇)cycloalkyl, wherein the cycloalkyl isunsubstituted or substituted by 1 to 2 (C₁₋₃)alkyl, or halo; or—(C₁₋₃)alkyl-heterocyclyl containing 1 or 2 heteroatoms independentlyselected from N and O, wherein the heterocyclyl is a 4-7 membered ring.3. The compound of claim 2, or a pharmaceutically acceptable saltthereof wherein: R³ is phenyl unsubstituted or substituted by 1 to 2halo.
 4. The compound of claim 2, or a pharmaceutically acceptable saltthereof wherein: R³ is six-membered heteroaryl containing 1 or 2 Nheteroatoms, wherein heteroaryl is unsubstituted or substituted by 1 to2 halo.
 5. The compound of claim 2, or a pharmaceutically acceptablesalt thereof wherein: R³ is (C₁₋₆)alkyl.
 6. The compound of claim 1, ora pharmaceutically acceptable salt thereof wherein R¹ is phenylunsubstituted or substituted by 1 to 3 halo; 6-membered heteroarylcontaining 1 to 2 N heteroatoms, wherein the heteroaryl is unsubstitutedor substituted by 1 to 2 halo, (C₁₋₃)alkyl, or halo(C₁₋₃)alkyl; or—(C₁₋₃)alkyl-phenyl, wherein phenyl is unsubstituted or substituted by 1to 3 halo.
 7. The compound of claim 6, or a pharmaceutically acceptablesalt thereof wherein: R³ is phenyl unsubstituted or substituted by 1 to2 halo.
 8. The compound of claim 6, or a pharmaceutically acceptablesalt thereof wherein: R³ is six-membered heteroaryl containing 1 or 2 N,wherein heteroaryl is unsubstituted or substituted by 1 to 2 halo. 9.The compound of claim 6, or a pharmaceutically acceptable salt thereofwherein: R³ is (C₁₋₆)alkyl.
 10. The compound of claim 1, or apharmaceutically acceptable salt thereof wherein: X is O.
 11. Thecompound of claim 1, or a pharmaceutically acceptable salt thereofwherein X is S.
 12. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof wherein: X is NH.
 13. The compound of claim 1,which is:4-Amino-2-[8-(3-fluorophenoxy)imidazo[1,2-a]pyrazin-6-yl]-5-(4-fluorophenyl)-5-methyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4-amino-5-(4-fluorophenyl)-5-methyl-2-[8-(2,2,3,3,3-pentafluoropropoxy)imidazo[1,2-a]pyrazin-6-yl]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4-amino-5-methyl-2-[8-(2,2,3,3,3-pentafluoropropoxy)imidazo[1,2-a]pyrazin-6-yl]-5-phenyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4-amino-2-[8-(2-fluorophenoxy)imidazo[1,2-a]pyrazin-6-yl]-5-(4-fluorophenyl)-5-methyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4-amino-2-[8-(2-fluorophenoxy)imidazo[1,2-a]pyrazin-6-yl]-5-methyl-5-phenyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4-amino-5-(4-fluorophenyl)-5-methyl-2-[8-(2,3,6-trifluorophenoxy)imidazo[1,2-a]pyrazin-6-yl]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4-amino-5-methyl-5-phenyl-2-[8-(2,3,6-trifluorophenoxy)imidazo[1,2-a]pyrazin-6-yl]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4-amino-2-[8-(3-fluorophenoxy)imidazo[1,2-a]pyrazin-6-yl]-5-methyl-5-phenyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4-amino-5-(4-fluorophenyl)-5-methyl-2-(8-phenoxyimidazo[1,2-a]pyrazin-6-yl)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4-amino-5-methyl-2-(8-phenoxyimidazo[1,2-a]pyrazin-6-yl)-5-phenyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4-amino-5-methyl-5-phenyl-2-[8-(2,3,4-trifluorophenoxy)imidazo[1,2-a]pyrazin-6-yl]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4-amino-5-methyl-5-phenyl-2-[8-(2,3,5-trifluorophenoxy)imidazo[1,2-a]pyrazin-6-yl]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4-amino-2-[8-(2,3-difluorophenoxy)imidazo[1,2-a]pyrazin-6-yl]-5-methyl-5-phenyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4-amino-5-cyclopropyl-5-(4-fluorophenyl)-2-[8-(2,2,3,3,3-pentafluoropropoxy)imidazo[1,2-a]pyrazin-6-yl]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4-amino-2-[8-(2,3-difluorophenoxy)imidazo[1,2-a]pyrazin-6-yl]-5-(4-fluorophenyl)-5-methyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4amino-5-(4-fluorophenyl)-5-methyl-2-[8-(2,3,4-trifluorophenoxy)imidazo[1,2-a]pyrazin-6-yl]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4-amino-5-(4-fluorophenyl)-5-methyl-2-[8-(2,3,5-trifluorophenoxy)imidazo[1,2-a]pyrazin-6-yl]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4-amino-2-[8-(3,4-difluorophenoxy)imidazo[1,2-a]pyrazin-6-yl]-5-(4-fluorophenyl)-5-methyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4-amino-2-[8-(2,4-difluorophenoxy)imidazo[1,2-a]pyrazin-6-yl]-5-(4-fluorophenyl)-5-methyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4-amino-2-[8-(4-fluorophenoxy)imidazo[1,2-a]pyrazin-6-yl]-5-(4-fluorophenyl)-5-methyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4-amino-5-(4-fluorophenyl)-5-methyl-2-(8-{[5-(trifluoromethyl)pyridin-3-yl]oxy}imidazo[1,2-a]pyrazin-6-yl)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4-amino-2-[8-(cyclohexyloxy)imidazo[1,2-a]pyrazin-6-yl]-5-(4-fluorophenyl)-5-methyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4-amino-2-[8-(3,5-difluorophenoxy)imidazo[1,2-a]pyrazin-6-yl]-5-(4-fluorophenyl)-5-methyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4-amino-2-[8-(3,5-difluorophenoxy)imidazo[1,2-a]pyrazin-6-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4-amino-2-[8-(2,5-difluorophenoxy)imidazo[1,2-a]pyrazin-6-yl]-5-(4-fluorophenyl)-5-methyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4-amino-2-[8-(2,5-difluorophenoxy)imidazo[1,2-a]pyrazin-6-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4amino-5-(4-chlorophenyl)-2-[8-(2,5-difluorophenoxy)imidazo[1,2-a]pyrazin-6-yl]-5-methyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4-amino-5-(4-chlorophenyl)-2-{8-[(4,4-difluorocyclohexyl)oxy]imidazo[1,2-a]pyrazin-6-yl}-5-methyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4-amino-5-(4-fluorophenyl)-5-methyl-2-[8-(pyridin-3-yloxy)imidazo[1,2-a]pyrazin-6-yl]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4-amino-5-(4-chlorophenyl)-5-methyl-2-[8-(pyridin-3-yloxy)imidazo[1,2-a]pyrazin-6-yl]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4-amino-2-{8-[(3,3-difluorocyclobutyl)methoxy]imidazo[1,2-a]pyrazin-6-yl}-5-(4-fluorophenyl)-5-methyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4-amino-5-(4-chlorophenyl)-2-{8-[(3,3-difluorocyclobutyl)methoxy]imidazo[1,2-a]pyrazin-6-yl}-5-methyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4-amino-2-{8-[(3,3-difluorocyclobutyl)methoxy]imidazo[1,2-a]pyrazin-6-yl}-5-(5-fluoropyridin-2-yl)-5-methyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4-amino-5-(4-fluorophenyl)-5-methyl-2-{8-[(2,2,3,3,3-pentafluoropropyl)amino]imidazo[1,2-a]pyrazin-6-yl}-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4-Amino-2-(8-(3-fluorophenoxy)-2-(trifluoromethyl)imidazo[1,2-a]pyrazin-6-yl)-5-(4-fluorophenyl)-5-methyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-(4-fluorophenyl)-5-methyl-2-(8-phenoxy-2-(trifluoromethyl)imidazo[1,2-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-2-(8-(2,3-difluorophenoxy)-2-(trifluoromethyl)imidazo[1,2-a]pyrazin-6-yl)-5-(4-fluorophenyl)-5-methyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-2-[2-cyclopropyl-8-(3-fluorophenoxy)imidazo[1,2-a]pyrazin-6-yl]-5-(4-fluorophenyl)-5-methyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4-Amino-5-(4-fluorophenyl)-5-methyl-2-(8-propoxyimidazo[1,2-a]pyrazin-6-yl)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4-Amino-5-(4-chlorophenyl)-2-{8-[(2-methoxyethyl)amino]imidazo[1,2-a]pyrazin-6-yl}-5-methyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4-amino-2-{8-[2-(2,2-difluorocyclopropyl)ethoxy]imidazo[1,2-a]pyrazin-6-yl}-5-(4-fluorophenyl)-5-methyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4-amino-2-{8-[2-(3,3-difluorocyclobutyl)ethoxy]imidazo[1,2-a]pyrazin-6-yl}-5-(4-fluorophenyl)-5-methyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,44-amino-2-[8-(cyclohexylmethoxy)imidazo[1,2-a]pyrazin-6-yl]-5-(4-fluorophenyl)-5-methyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4-amino-2-[8-(2-cyclopropylethoxy)imidazo[1,2-a]pyrazin-6-yl]-5-(4-fluorophenyl)-5-methyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4-amino-2-[8-(cyclopentylmethoxy)imidazo[1,2-a]pyrazin-6-yl]-5-(4-fluorophenyl)-5-methyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4-amino-2-[8-(cyclopentyloxy)imidazo[1,2-a]pyrazin-6-yl]-5-(4-fluorophenyl)-5-methyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4-amino-5-(4-chlorophenyl)-5-methyl-2-[8-(2,2,3,3,3-pentafluoropropoxy)imidazo[1,2-a]pyrazin-6-yl]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4-amino-2-[8-(benzyloxy)imidazo[1,2-a]pyrazin-6-yl]-5-(4-chlorophenyl)-5-methyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4-amino-5-(4-chlorophenyl)-5-methyl-2-(8-propoxyimidazo[1,2-a]pyrazin-6-yl)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4-amino-5-(4-chlorophenyl)-2-[8-(2-cyclopropylethoxy)imidazo[1,2-a]pyrazin-6-yl]-5-methyl-5,7-dihydro-6H-pyrrolo[2,3-a]pyrimidin-6-one,4-amino-5-(4-fluorophenyl)-5-methyl-2-[8-(2-methylpropoxy)imidazo[1,2-a]pyrazin-6-yl]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4-amino-5-(4-fluorophenyl)-2-{8-[(2-methoxyethyl)amino]imidazo[1,2-a]pyrazin-6-yl}-5-methyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4-amino-2-(8-{[(3,3-difluorocyclobutyl)methyl]amino}imidazo[1,2-a]pyrazin-6-yl)-5-(4-fluorophenyl)-5-methyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4-amino-2-(8-{[(1-ethylcyclopropyl)methyl]amino}imidazo[1,2-a]pyrazin-6-yl)-5-(4-fluorophenyl)-5-methyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4-amino-2-{8-[(cyclohexylmethyl)amino]imidazo[1,2-a]pyrazin-6-yl}-5-(4-fluorophenyl)-5-methyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4-amino-5-(4-chlorophenyl)-2-(8-{[(2,2-dimethylcyclopropyl)methyl]amino}imidazo[1,2-a]pyrazin-6-yl)-5-methyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4-amino-5-(4-chlorophenyl)-2-(8-{[(1-ethylcyclopropyl)methyl]amino}imidazo[1,2-a]pyrazin-6-yl)-5-methyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4-amino-5-(4-chlorophenyl)-2-(8-{[(3,3-difluorocyclobutyl)methyl]amino}imidazo[1,2-a]pyrazin-6-yl)-5-methyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4-amino-5-(4-chlorophenyl)-5-methyl-2-{8-[(tetrahydro-2H-pyran-4-ylmethyl)amino]imidazo[1,2-a]pyrazin-6-yl}-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4-amino-2-[8-(benzylamino)imidazo[1,2-a]pyrazin-6-yl]-5-(4-chlorophenyl)-5-methyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4-amino-5-(4-chlorophenyl)-5-methyl-2-{8-[(2,2,3,3,3-pentafluoropropyl)amino]imidazo[1,2-a]pyrazin-6-yl}-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4-amino-5-(4-fluorophenyl)-5-methyl-2-[8-(propylsulfanyl)imidazo[1,2-a]pyrazin-6-yl]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4-amino-5-(4-fluorophenyl)-5-methyl-2-{8-[(2-methylpropyl)sulfanyl]imidazo[1,2-a]pyrazin-6-yl}-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4-amino-5-(4-fluorophenyl)-5-methyl-2-{8-[(3,3,3-trifluoropropyl)sulfanyl]imidazo[1,2-a]pyrazin-6-yl}-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4-amino-5-(4-fluorophenyl)-5-methyl-2-[8-(1-methylbutoxy)imidazo[1,2-a]pyrazin-6-yl]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4-amino-5-(4-chlorophenyl)-5-methyl-2-[8-(tetrahydro-2H-pyran-3-ylmethoxy)imidazo[1,2-a]pyrazin-6-yl]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4-amino-5-(4-chlorophenyl)-5-methyl-2-[8-(tetrahydro-2H-pyran-3-ylmethoxy)imidazo[1,2-a]pyrazin-6-yl]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4-amino-5-(4-chlorophenyl)-5-methyl-2-[8-(tetrahydro-2H-pyran-2-ylmethoxy)imidazo[1,2-a]pyrazin-6-yl]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4-amino-5-(4-chlorophenyl)-5-methyl-2-{8-[(1S)-1-phenylethoxy]imidazo[1,2-a]pyrazin-6-yl}-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4-amino-5-(4-chlorophenyl)-5-methyl-2-{8-[(tetrahydro-2H-pyran-2-ylmethyl)amino]imidazo[1,2-a]pyrazin-6-yl}-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4-amino-5-(4-chlorophenyl)-5-methyl-2-{8-[(tetrahydro-2H-pyran-3-ylmethyl)amino]imidazo[1,2-a]pyrazin-6-yl}-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4-amino-5-(4-chlorophenyl)-5-methyl-2-{8-[(1-phenylethyl)amino]imidazo[1,2-a]pyrazin-6-yl}-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,or4-amino-5-(4-chlorophenyl)-5-methyl-2-{8-[(1-phenylethyl)amino]imidazo[1,2-a]pyrazin-6-yl}-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,or a pharmaceutically acceptable salt thereof.
 14. A method foractivating soluble guanylate cyclase comprising the step ofadministering an amount efficacious therefor of the compound of any oneof claim 1 or a pharmaceutically acceptable salt thereof to a patient inneed thereof.
 15. A method for the treatment of one or more conditionsselected from cardiovascular disease, endothelial dysfunction, diastolicdysfunction, atherosclerosis, hypertension, heart failure, pulmonaryhypertension, angina pectoris, thrombosis, restenosis, myocardialinfarction, stroke, cardiac insufficiency, fibrosis, pulmonaryhypertonia, erectile dysfunction, asthma bronchiale, chronic kidneydisease, diabetes or cirrhosis of the liver comprising administering atherapeutically effective amount of the compound of claim 1, or apharmaceutically acceptable salt thereof, to a patient in need thereof.16. A method for the treatment of hypertension comprising administeringa therapeutically effective amount of the compound of claim 1, or apharmaceutically acceptable salt thereof, to a patient in need thereof.17. A method for the treatment of heart failure comprising administeringa therapeutically effective amount of the compound of claim 1, or apharmaceutically acceptable salt thereof, to a patient in need thereof.18. A pharmaceutical composition comprised of the compound of claim 1,or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.
 19. The pharmaceutical composition of claim 18further comprising one or more additional active agents.
 20. Thepharmaceutical composition of claim 19 wherein the one or moreadditional active agents is selected from an angiotensin convertingenzyme inhibitor, an angiotensin II receptor antagonist, a neutralendopeptidase inhibitor, an aldosterone antagonist, a renin inhibitor,an endothelin receptor antagonist, an aldosterone synthase inhibitor, aphosphodiesterase-5 inhibitor, a vasodilator, a calcium channel blocker,a potassium channel activator, a diuretic, a sympatholitic, abeta-adrenergic blocking drug, an alpha adrenergic blocking drug, acentral alpha adrenergic agonist, a peripheral vasodilator, a lipidlowering agent or a metabolic altering agent. 21-22. (canceled)